IMPORTANCE Multiple systemic treatments are available for metastatic castration-sensitive prostate cancer (mCSPC), with unclear comparative effectiveness and safety and widely varied costs.OBJECTIVE To compare the effectiveness and safety determined in randomized clinical trials of systemic treatments for mCSPC. DATA SOURCES Bibliographic 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 SYNTHESIS Eligible 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).RESULTS Seven 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,), 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.
Background For nonmetastatic castration-resistant prostate cancer (nmCRPC), three drugs under patent protection—apalutamide, enzalutamide, and darolutamide—were approved based on randomized, placebo-controlled trials; one drug with generic availability—abiraterone acetate—showed efficacy in a single-arm trial and is commonly prescribed. Lacking head-to-head trials, the optimal treatment for nmCRPC is unknown, despite widely varied treatment costs. We compared the efficacy and safety of nmCRPC treatments. Methods We searched bibliographic databases, regulatory documents, and trial registries for nmCRPC trials. We included published results and, when available original data. We performed matching-adjusted indirect comparison and network meta-analysis and compared treatments regarding metastasis-free survival (MFS), overall survival (OS), and serious adverse events (SAE). Results We analyzed five trials with a total of 4,360 participants. Compared with placebo, abiraterone acetate engendered the lowest hazard of metastasis/death (hazard ratio [HR] = 0.22, 95% credible interval [CrI] = 0.12 to 0.41), followed by apalutamide (HR = 0.28, 95% CrI=0.23 to 0.34), enzalutamide (HR = 0.30, 95% CrI=0.25 to 0.36), darolutamide (HR = 0.41, 95% CrI=0.34 to 0.49); darolutamide led to the lowest hazard of death (HR = 0.69, 95% CrI= 0.53 to 0.90), followed by enzalutamide (HR = 0.73, 95% CrI=0.61 to 0.87) and apalutamide (HR = 0.75, 95% CrI=0.59 to 0.95); darolutamide resulted in the lowest odds of SAEs (odds ratio [OR] = 1.32, 95% CrI= 1.02 to 1.70), followed by enzalutamide (OR = 1.43, 95% CrI=1.08 to 1.89), apalutamide (OR = 1.58, 95% CrI=1.23 to 2.03), and abiraterone acetate (OR = 1.94, 95% CrI=1.17 to 3.22). Conclusions For nmCRPC, darolutamide offered optimal efficacy and safety among approved drugs, abiraterone acetate may offer comparable MFS benefit with cost-savings from generic availability. Future research is needed to more fully examine abiraterone acetate's benefit.
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