Dataset Information

Combination therapy in metastatic castration sensitive prostate cancer: A Systematic review and network meta-analysis.

ABSTRACT:

Introduction

Studies directly comparing the different combination therapies offered to men with metastatic castration sensitive prostate cancer (mCSPC), are not available yet. This study was designed using the network meta-analysis (NMA) framework to provide a comparison of the different available options for the treatment of men with mCSPC.

Methods

A systematic search was performed and the prospective randomized controlled trials reporting the overall survival (OS) or failure-free survival (FFS) were selected for review. A total of 14 studies were included in the NMA.

Results

The addition of abiraterone, apalutamide, docetaxel, and docetaxel with zoledronic acid to the androgen deprivation therapy (ADT) demonstrated a significant improvement in the OS. In indirect comparison, abiraterone had a higher impact on the OS as compared to docetaxel (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 1.0-1.46) and docetaxel with zoledronic acid (HR: 1.31, 95% CI: 1.05-1.63) but not apalutamide. Furthermore, apalutamide was not different than docetaxel or docetaxel with zoledronic acid. There was a significant improvement in the FFS with the combination of abiraterone, apalutamide, docetaxel (HR: 0.61, 95% CI: 0.46-0.81), docetaxel with zoledronic acid (HR: 0.62, 95% CI: 0.43-0.9), and enzalutamide (HR: 0.39, 95% CI: 0.25-0.61) as compared to the ADT alone. Similar to the indirect comparison of OS, abiraterone outperformed docetaxel (HR: 1.66, 95% CI: 1.12-2.47), docetaxel with zoledronic acid (HR: 1.69, 95% CI: 1.06-2.68), and enzalutamide (HR: 1.06, 95% CI: 0.63-1.80), but not apalutamide in terms of impact on the FFS.

Conclusion

Overall, abiraterone demonstrated better OS and FFS outcomes as compared to all the other combination strategies in this NMA.

SUBMITTER: Kumar J

PROVIDER: S-EPMC9380455 | biostudies-literature | 2022 Jul-Sep

REPOSITORIES: biostudies-literature

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Publications

Combination therapy in metastatic castration sensitive prostate cancer: A Systematic review and network meta-analysis.

Kumar Jatinder J Alam Muhammad Umar MU Jazayeri Seyed Behzad SB Tanneru Karthik K Bazargani Soroush S Shastri Charu C Gautam Shiva S Koochekpour Shahriar S Shukla Sanjeev S Bandyk Mark M Costa Joseph J Balaji K C KC

Indian journal of urology : IJU : journal of the Urological Society of India 20220701 3

<h4>Introduction</h4>Studies directly comparing the different combination therapies offered to men with metastatic castration sensitive prostate cancer (mCSPC), are not available yet. This study was designed using the network meta-analysis (NMA) framework to provide a comparison of the different available options for the treatment of men with mCSPC.<h4>Methods</h4>A systematic search was performed and the prospective randomized controlled trials reporting the overall survival (OS) or failure-fre ...[more]

PMID: 35983120

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Project description:ImportanceMultiple systemic treatments are available for metastatic castration-sensitive prostate cancer (mCSPC), with unclear comparative effectiveness and safety and widely varied costs.ObjectiveTo compare the effectiveness and safety determined in randomized clinical trials of systemic treatments for mCSPC.Data sourcesBibliographic databases (MEDLINE, Embase, and Cochrane Central), regulatory documents (US Food and Drug Administration and European Medicines Agency), and trial registries (ClinicalTrials.gov and European Union clinical trials register) were searched from inception through November 5, 2019.Study selection, data extraction, and synthesisEligible studies were randomized clinical trials evaluating the addition of docetaxel, abiraterone acetate, apalutamide, or enzalutamide to androgen-deprivation therapy (ADT) for treatment of mCSPC. Two investigators independently performed screening. Discrepancies were resolved through consensus. A Cochrane risk-of-bias tool was used to assess trial quality. Relative effects of competing treatments were assessed by bayesian network meta-analysis and survival models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used.Main outcomes and measuresOverall survival, radiographic progression-free survival, and serious adverse events (SAEs).ResultsSeven trials with 7287 patients comparing 6 treatments (abiraterone acetate, apalutamide, docetaxel, enzalutamide, standard nonsteroidal antiandrogen, and placebo/no treatment) were identified. Ordered from the most to the least effective determined by results of clinical trials, treatments associated with improved overall survival when added to ADT included abiraterone acetate (hazard ratio [HR], 0.61; 95% credible interval [CI], 0.54-0.70), apalutamide (HR, 0.67; 95% CI, 0.51-0.89), and docetaxel (HR, 0.79; 95% CI, 0.71-0.89); treatments associated with improved radiographic progression-free survival when added to ADT included enzalutamide (HR, 0.39; 95% CI, 0.30-0.50), apalutamide (HR, 0.48; 95% CI, 0.39-0.60), abiraterone acetate (HR, 0.51; 95% CI, 0.45-0.58), and docetaxel (HR, 0.67; 95% CI 0.60-0.74). Docetaxel was associated with substantially increased SAEs (odds ratio, 23.72; 95% CI, 13.37-45.15), abiraterone acetate with slightly increased SAEs (odds ratio, 1.42; 95% CI, 1.10-1.83), and other treatments with no significant increase in SAEs. Risk of bias was noted for 4 trials with open-label design, 3 trials with missing data, and 2 trials with potential unprespecified analyses.Conclusions and relevanceIn this network meta-analysis, as add-on treatments to ADT, abiraterone acetate and apalutamide may provide the largest overall survival benefits with relatively low SAE risks. Although enzalutamide may improve radiographic progression-free survival to the greatest extent, longer follow-up is needed to examine the overall survival benefits associated with enzalutamide.

Project description:ImportanceThe effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown.ObjectiveTo assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups.Data sourcesFor this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available.Study selectionPhase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC.Data extraction and synthesisTwo independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022.Main outcomes and measuresOutcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life.ResultsThis report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT.Conclusions and relevanceThe potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Project description:Purpose: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available docetaxel-based systemic triplet therapies for metastatic hormone-sensitive prostate cancer (mHSPC). Methods: We searched for eligible publications in PubMed, Embase, and Cochrane CENTRAL. Improvements in overall survival (OS) and radiographic progression-free time (rPFS) were compared indirectly using network meta-analysis and evaluated using the surface under the cumulative ranking curve (SUCRA). Other secondary endpoints, such as time to castration-resistant prostate cancer and/or adverse events (AEs), were also compared and evaluated. Results: Five trials were selected and analyzed using a network meta-analysis. Compared to androgen deprivation therapy (ADT) plus docetaxel, darolutamide (hazard ratio [HR]: 0.68, 95% credible interval [CrI]: 0.57-0.80) and abiraterone (HR: 0.75, 95% CrI: 0.59-0.95) triplet therapy had significantly longer OS, and darolutamide triplet therapy was the first treatment ranked. Abiraterone (HR: 0.49, 95% CrI: 0.39-0.61) and enzalutamide (HR: 0.52, 95% CrI: 0.30-0.89) had significantly better rPFS than ADT plus docetaxel; however, all three therapies, including abiraterone, apalutamide, and enzalutamide, were the best options with a similar SUCRA. At most secondary endpoints, systemic triplet therapy was superior to ADT plus docetaxel. The risk of any AEs in darolutamide or abiraterone triplet therapy was comparable with ADT plus docetaxel (odds ratio [OR]: 2.53, 95% credible interval [CrI]: 0.68-12.63; OR: 1.07, 95% CrI: 0.03-36.25). Abiraterone triplet therapy had an increased risk of grade≥3 AEs (OR: 1.56, 95% CrI: 1.15-2.11). Conclusion: Systemic triplet therapy was more effective than ADT plus docetaxel for mHSPC. Of the triplet therapy regimens, darolutamide ranked first in terms of improved OS. Abiraterone and enzalutamide triplet ranked first in terms of rFPS, however, it did not confer a statistically difference among all triplet regimens. The overall risk of AEs was comparable. More studies are required for current and potential combinations of systemic triplet therapy.

Project description:Purpose: To conduct a systematic review and network meta-analysis (NMA) to compare the efficacy of currently available combination therapies in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Methods: Qualified publications were searched in the PubMed, Embase, and Cochrane CENTRAL databases. Overall survival (OS) and radiographic progression-free survival (rPFS) were indirectly compared and assessed using NMA and the surface under the cumulative ranking curve, respectively. Adverse events (AEs) were also compared. Results: Eighteen publications from 12 trials were analyzed in the NMA. In the overall population, triplet therapy was ranked first for OS (hazard ratio [HR]: 0.57, 95% credible interval [CrI]: 0.48-0.67) and rPFS (HR: 0.33, 95% CrI:0.26-0.41) compared with androgen deprivation therapy (ADT) with or without standard non-steroidal antiandrogen. In high-volume mHSPC, triplet therapy was also ranked first in OS (HR, 0.57; 95% CrI:0.44-0.75) and rPFS(HR, 0.29; 95% CrI: 0.23-0.37). Specifically, abiraterone triplet therapy was ranked first in OS (HR, 0.52; 95% CrI:0.38-0.72) and rPFS (HR, 0.28; 95% CrI:0.21-0.38) among all therapies. ADT plus rezvilutamide was ranked first among doublet therapies (OS: HR, 0.58; 95% CrI:0.44-0.77; rPFS: HR, 0.44; 95% CrI:0.33-0.58). In low-volume mHSPC, doublet and triplet therapies were ranked first in OS (HR:0.68, 95% CrI:0.58-0.80) and rPFS (HR:0.37, 95% CrI:0.25-0.55), respectively. ADT plus apalutamide was ranked first in OS among all therapies (HR:0.53, 95% CrI:0.35-0.79), whereas enzalutamide triplet therapy was ranked first in rPFS (HR:0.27, 95% CrI:0.15-0.51). ADT plus rezvilutamide showed a relatively lower incidence of AE among all therapies (OR:1.00, 95% CrI:0.31-3.15), and a lower risk of specific AEs among doublet therapies, particularly regarding seizure (OR, 0.29; 95% CrI:0.01-8.18) and fatigue (OR, 0.96; 95% CrI:0.63-1.46). Docetaxel-based doublet or triplet therapies significantly increased the risk of any AEs or grade ≥3 AEs. Conclusion: Triplet therapy was the best treatment option for the overall population. In high-volume mHSPC, triplet therapy and ADT plus rezvilutamide had the greatest potential to benefit patients. Patients with low-volume mHSPC were most likely to benefit from ADT plus androgen receptor-targeted agents. Triplet therapy was associated with a higher risk of AEs than the other therapies. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022375347, identifier PROSPERO:CRD42022375347.

Project description:IntroductionEnzalutamide, apalutamide, and darolutamide have all been approved by Food and Drug Administration to treat high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) since 2018 based on interim results of several phase III clinical trials. Final analyses of long-term overall survival (OS) and adverse events (AEs) results of these trials have been successively published recently. To help clinical practice to precisely select optimal treatment for high-risk nmCRPC patients, we performed a network meta-analysis to indirectly compare the final long-term results among these medications.MethodsPubMed, EMBASE, and Cochrane Libraries were searched for phase III clinical trial that reports OS and AEs results in nmCRPC patients published before January 30, 2021. Primary outcome was OS; secondary outcomes were Time to first chemotherapy, Subsequent antineoplastic therapy rate, and AEs. Firstly, class-level effect was assessed as the second-generation androgen receptor antagonists (SGARAs) were regarded as one whole class compared with placebo through traditional meta-analysis by using Revman 5.4, then a Bayesian network meta-analysis was conducted to give indirect comparison among SGARAs by using R 3.5.3 software. Subgroup analysis of OS was only conducted in the certain subgroups which were available in all included studies.ResultsThree eligible studies including 4,104 participants were finally selected. OS was significantly improved by the SGARAs as a class compared with placebo (HR, 0.74; 95% CI, 0.66-0.84). Darolutamide had the highest likelihood of providing best OS (p-score=0.802). SGARAs also significantly delayed the first time to chemotherapy (HR, 0.58; 95% CI, 0.50-0.66). Patients who received darolutamide experienced similar toxicity compared with placebo regarding AEs of grade 3 or higher (OR, 1.3; 95% CI, 1.0-1.7) and serious AEs (OR, 1.3; 95% CI, 0.99-1.6). When compared with darolutamide, enzalutamide caused significantly higher toxicity in terms of any AEs (OR, 2.3; 95% CI,1.5-3.7) and AEs of grade 3 or higher (OR, 1.6; 95% CI, 1.1-2.2), apalutamide caused significantly more AEs of grade 3 or higher (OR, 1.9; 95% CI, 1.4-2.7) and serious AEs (OR, 1.9; 95% CI, 1.3-2.8). Subgroup analysis showed that SGARAs as a group significantly improved OS in ECOG=1 population, although insignificant results were found in these patients from included studies.ConclusionsSGARAs combined with ADT significantly improved OS when compared with ADT alone in high-risk nmCRPC patients. Darolutamide may not only provide best OS but also have the most favorable safety profile among the included SGARAs in high-risk nmCRPC patients.

Project description:Background: Recent randomized clinical trials have examined the efficacy of different combinations of systemic and local treatment approaches for metastatic hormone-sensitive prostate cancer (mHSPC). We compared the efficacy of these combined regimens in order to identify the optimal therapy for specific patient subgroups. Methods: The treatments were abiraterone (ABI), apalutamide (APA), docetaxel (DOC), enzalutamide (ENZ), and radiotherapy (RT) combined with androgen-deprivation therapy (ADT). Five electronic databases were searched up to May 7, 2020 for relevant trials. The risk of bias in the included trials was evaluated with the Cochrane tool. The hazard ratio (HR) with 95% confidence interval (CI) was determined for the included trials and indirect comparisons were performed using the R software. Results: In total, 10 randomized, controlled trials with 11,194 patients were included in the meta-analysis. ADT + RT was superior to ADT monotherapy in terms of overall survival (HR = 0.96, 95% CI: 0.85-1.1) and conferred a survival benefit in a subgroup of low-volume patients (HR = 0.68, 95% CI: 0.54-0.87). Combined systemic treatments were significantly superior to ADT monotherapy in comparisons of survival and prostate-specific antigen response, including in the high-volume subgroup; meanwhile, in the low-volume subgroup only ADT + ENZ (HR = 0.38, 95% CI 0.21-0.69) showed a significant clinical benefit. In the Gleason score <8 subgroup, all combined systemic treatments were superior to ADT monotherapy, but the results were only significant for ADT + APA (HR = 0.56, 95% CI: 0.33-0.95) and ADT + DOC (HR = 0.71, 95% CI: 0.54-0.92). In the Gleason score ≥8 subgroup, ADT monotherapy was inferior (albeit not significantly) to combined treatments. In a ranking of performed comparisons, ADT + ENZ was the optimal regimen, although this was non-significant. Combined therapies also demonstrated superiority in quality-of-life indicators such as time to skeletal events and pain progression. Conclusion: ADT + radiotherapy led to superior outcomes in mHSPC patients with low-volume disease. While all combined systemic regimens confer a survival advantage over ADT monotherapy, the optimal treatment approach for certain mHSPC patient subgroups remains to be determined.

Project description:Background: Lacking head-to-head trial, the optimal treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure is unclear. This study is to compare the efficacy and safety of systemic treatments in patients who progressed after docetaxel to aid clinical decision-making. Methods: Databases including MEDLINE, EMBASE, and the Cochrane Library were searched from inception to June 15th, 2021. The outcomes of interest include overall survival (OS), biochemical progression-free survival (bPFS), and serious adverse events (SAEs). The Cochrane risk of bias tools were used to assess study quality. Indirect comparisons of competing treatments were performed via Bayesian network meta-analysis. Results: Five trials with 3,862 patients comparing four treatments (abiraterone, enzalutamide, cabazitaxel, and radium-223) were identified. All the four treatments were associated with improved OS and bPFS relative to best supportive care. Among them, enzalutamide (hazard ratio [HR] = 0.58, 95% credible interval [Crl]: 0.49-0.69) had the highest probability of ranking first in terms of OS, followed by cabazitaxel (HR = 0.70, 95% Crl: 0.59-0.83), radium-223 (HR = 0.71, 95% Crl: 0.56-0.90) and abiraterone (HR = 0.73, 95% Crl: 0.63-0.84). Similarly, enzalutamide (HR = 0.25, 95% Crl: 0.20-0.31) showed the greatest improvement of bPFS, followed by abiraterone (HR = 0.60, 95% Crl: 0.51-0.71) and cabazitaxel (HR = 0.75, 95% Crl: 0.63-0.89). In terms of safety, treatments ranked from the safest to the least safe were radium-223 (OR = 0.58, 95% Crl: 0.20-1.68), enzalutamide (OR = 0.80, 95% Crl: 0.28-2.29), abiraterone (OR = 0.94, 95% Crl: 0.39-2.27) and cabazitaxel (OR = 2.50, 95% Crl: 0.84-7.44). Conclusion: For patients with mCRPC who progressed after docetaxel, enzalutamide may offer the most significant survival benefits and satisfying safety. Cabazitaxel is effective in post-docetaxel settings but associated with a high risk of SAEs. Although network meta-analysis provides indirect comparisons and ranking probabilities, the results should be treated with caution as it cannot replace randomized direct comparison. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020223040, identifier CRD42020223040.

Dataset Information

Combination therapy in metastatic castration sensitive prostate cancer: A Systematic review and network meta-analysis.

Introduction

Methods

Results

Conclusion

Publications

Combination therapy in metastatic castration sensitive prostate cancer: A Systematic review and network meta-analysis.

Similar Datasets

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