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Original Investigation
January 14, 2021

Comparison of Systemic Treatments for Metastatic Castration-Sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis

Author Affiliations
  • 1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 2Center for Drug Safety and Effectiveness, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
  • 3Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 4Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
  • 5Duke Clinical Research Institute, Duke University, Durham, North Carolina
JAMA Oncol. 2021;7(3):412-420. doi:10.1001/jamaoncol.2020.6973
Key Points

Question  What are the most effective systemic treatments for metastatic castration-sensitive prostate cancer?

Findings  This network meta-analysis of 7 randomized clinical trials including 7287 patients noted that, combined with androgen-deprivation therapy, treatments associated with significantly improved overall survival included abiraterone acetate, apalutamide, and docetaxel; treatments associated with significantly improved radiographic progression-free survival included enzalutamide, abiraterone acetate, apalutamide, and docetaxel, ordered from the agent with the greatest to least effectiveness according to the results of clinical trials. Docetaxel was associated with substantially increased serious adverse events, abiraterone with slightly increased serious adverse events, and other treatments with no increase in serious adverse events.

Meaning  This network meta-analysis suggests that abiraterone acetate and apalutamide may provide the largest and most consistent overall survival benefits with relatively low serious adverse event risks among metastatic castration-sensitive prostate cancer treatments.


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 Measures  Overall 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, 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 Relevance  In 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.

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