Two randomized controlled trials recently demonstrated an overall survival benefit with triplet therapy (androgen receptor axis-targeted agent [ARAT] + docetaxel + androgen deprivation therapy [ADT]) over doublet therapy (docetaxel + ADT) in metastatic hormone-sensitive prostate cancer (mHSPC), broadening the treatment options. In our previous systematic review and network meta-analysis on the role of triplet versus doublet therapy, we focused on ARAT + ADT, as this is the actual standard of care in many countries for mHSPC. However, survival data by disease volume were only available for one triplet therapy regimen (PEACE-1). Survival data stratified by disease volume for a second triplet regimen (ARASENS) are now available, hence we updated our meta-analysis for low- and high-volume mHSPC. Consistent with previous findings, ADT alone no longer represents a valid treatment option for mHSPC. Similar considerations apply to doublet therapy with docetaxel + ADT. For low-volume mHSPC, in comparison to ADT, the benefit of combination therapies other than ARAT + ADT was not substantial. For high-volume mHSPC, darolutamide + docetaxel + ADT ranked first (P score 0.92), followed by abiraterone + docetaxel + ADT (P score 0.85) and then ARAT + ADT combination therapies. In high-volume mHSPC, only darolutamide + docetaxel + ADT demonstrated superior overall survival (hazard ratio 0.76, 95% confidence interval 0.59-0.97) versus (pooled) ARAT + ADT, confirming the importance of triplet therapy in (high-volume) mHSPC. PATIENT SUMMARY: We performed an updated comparison of double and triple therapy options for metastatic prostate cancer that still responds to hormone treatment. For patients with low-volume cancer, there was no significant survival benefit from addition of a third drug. For patients with high-volume cancer, the best survival was obtained with darolutamide + docetaxel + androgen deprivation therapy.
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