Comparison of Doublet and Triplet Therapies for Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Network Meta-Analysis

Background: The best choice of first-line treatment for metastatic hormone-sensitive prostate cancer (mHSPC) is unclear. We aimed to compare the effectiveness and safety determined in randomized clinical trials of doublet and triplet treatments for mHSPC. Methods: Medline, Embase, Cochrane Central and ClinicalTrials.gov were searched from inception through July 01, 2022. Eligible studies were phase III randomized clinical trials evaluating androgen deprivation treatment (ADT) alone, doublet therapies [ADT combined with docetaxel (DOC), novel hormonal agents (NHAs), or radiotherapy (RT)], or triplet therapies (NHA+DOC+ADT) as first-line treatments for mHSPC. Outcomes of interest included overall survival (OS), progression-free survival (PFS) and grades 3-5 adverse events (AEs). Subgroup analyses were performed based on tumor burden. The effects of competing treatments were assessed by Bayesian network meta-analysis using R software. Results: Ten trials with 12,298 patients comparing nine treatments were included. Darolutamide (DARO) +DOC+ADT ranked best in terms of OS benefits (OR 0 center dot 52 [95% CI 0 center dot 39-0 center dot 70]), but its advantages were all statistically insignificant compared with other therapy options except for DOC+ADT (OR 0 center dot 68 [95% CI 0 center dot 53-0 center dot 88]) and RT+ADT (OR 0 center dot 57 [95% CI 0 center dot 40-0 center dot 80]). In terms of PFS, enzalutamide( ENZA)+ DOC+ADT (OR 0 center dot 32 [95% CI 0 center dot 24-0 center dot 44]) and abiraterone and prednisone (AAP) +DOC+ADT (OR 0 center dot 33 [95% CI 0 center dot 25-0 center dot 45]) ranked best. For patients with high volume disease (HVD), low volume disease (LVD), and visceral metastases, the optimal therapies were AAP+DOC+ADT (OR 0 center dot 52 [95% CI 0 center dot 33-0 center dot 83]), apalutamide+ADT (OR 0 center dot 52 [95% CI 0 center dot 26-1 center dot 05]) and DARO+DOC+ADT (OR 0 center dot 42 [95% CI 0 center dot 13-1 center dot 34]), respectively. For safety, AAP+DOC+ADT (OR 3 center dot 56 [95% CI 1 center dot 51-8 center dot 43]) ranked worst with the highest risk of grade 3-5 AEs. Conclusions: Triple therapies may further improve OS and PFS but may be associated with a decrease in safety. Triplet therapies could be suggested for HVD patients, while doublet combinations should still be preferred for LVD patients.