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What are the most effective systemic treatments for metastatic castration-sensitive prostate cancer?
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.
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.
Multiple systemic treatments are available for metastatic castration-sensitive prostate cancer (mCSPC), with unclear comparative effectiveness and safety and widely varied costs.
To compare the effectiveness and safety determined in randomized clinical trials of systemic treatments for mCSPC.
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).
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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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: October 8, 2020.
Published Online: January 14, 2021. doi:10.1001/jamaoncol.2020.6973
Corresponding Author: Otis Brawley, MD, Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 1550 Orleans St, Baltimore, MD 21231 (firstname.lastname@example.org).
Author Contributions: Dr Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Wang, Paller, Hong, Brawley.
Acquisition, analysis, or interpretation of data: Wang, Hong, De Felice, Alexander.
Drafting of the manuscript: Wang, De Felice, Brawley.
Critical revision of the manuscript for important intellectual content: Wang, Paller, Hong, Alexander.
Statistical analysis: Wang, Hong.
Obtained funding: Wang.
Administrative, technical, or material support: Paller, Brawley.
Supervision: Alexander, Brawley.
Conflict of Interest Disclosures: Dr Wang reported receiving grants from the Dyar Memorial Fund and the Pharmaceutical Research and Manufacturers of America Foundation during the conduct of the study. Dr Alexander reported Dr Alexander is past chair of US Food and Drug Administration’s Peripheral and Central Nervous System Advisory Committee; has served as a paid adviser to IQVIA; is a cofounding principal and equity holder in Monument Analytics, a health care consultancy whose clients include the life sciences industry as well as plaintiffs in opioid litigation; and is a member of OptumRx's National P&T Committee. Dr Brawley reported receiving grants from the US National Cancer Institute during the conduct of the study and personal fees from Genentech outside the submitted work. No other disclosures were reported.
Funding/Support: This work was supported by the Dyar Memorial Fund and Pharmaceutical Research and Manufacturers of America Foundation 2020 Predoctoral Fellowship in Health Outcomes Research (Dr Wang).
Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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