Comparative efficacy and safety of nonhormonal prescription drugs for vasomotor symptoms in women with breast cancer: a systematic review and network meta-analysis

Background Vasomotor symptoms (VMS) are common during and after breast cancer treatment, particularly among women receiving endocrine therapy. We compared the efficacy, acceptability, and safety of nonhormonal prescription pharmacological interventions for VMS in women with breast cancer or breast cancer survivors. Methods We searched major databases and trial registries through July 2026 for randomized controlled trials comparing nonhormonal prescription drugs versus placebo or another eligible nonhormonal prescription drug in adult women with breast cancer-related VMS. The primary outcome was continuous VMS efficacy. Secondary outcomes included responder outcomes, all-cause discontinuation, discontinuation due to adverse events, any adverse events, and serious adverse events. We performed frequentist random-effects network meta-analysis, with Bayesian network meta-analysis as sensitivity analysis. Risk of bias was assessed using RoB 2, and certainty of evidence using a GRADE/NMA-GRADE approach. Results Eighteen publications, corresponding to 19 study/substudy records and 2,224 randomized or allocated participants, were included. Five interventions were significantly more effective than placebo: escitalopram (SMD -1.08, 95% CI -1.80 to −0.37), desvenlafaxine 50 mg (SMD -0.87, 95% CI -1.60 to −0.15), desvenlafaxine 100 mg (SMD -0.80, 95% CI -1.44 to −0.15), elinzanetant (SMD -0.51, 95% CI -0.95 to −0.07), and venlafaxine 75 mg (SMD -0.42, 95% CI -0.76 to −0.07). Heterogeneity was moderate (I 2 = 44.9%), with no significant global or local inconsistency. Frequentist P-scores ranked the five significant drugs top, confirmed by Bayesian sensitivity. Elinzanetant had high-certainty evidence, whereas venlafaxine 75 mg and gabapentin 900 mg had moderate-certainty evidence. Escitalopram and desvenlafaxine had large effects, but the supporting evidence was sparse. Discontinuation outcomes showed no statistically significant differences versus placebo, but sparse safety networks precluded a reliable comparative safety hierarchy; these null findings should not be interpreted as evidence of equivalent tolerability. Conclusion Nonhormonal prescription drugs are not interchangeable for breast cancer-related VMS. Elinzanetant provides the strongest high-certainty evidence among newer targeted options, and venlafaxine 75 mg is the best-supported conventional option. Escitalopram and desvenlafaxine remain promising but require further trials. Gabapentin 900 mg may be considered in selected patients, whereas sertraline, bupropion, gabapentin 300 mg, and clonidine are lower-priority options. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261460108 , identifier CRD420261460108.