Importance Electronic patient-reported outcome (PRO) monitoring has shown benefits in advanced cancer, but data specific to metastatic breast cancer (mBC) remain limited. Fatigue is a common, clinically important, and functionally impairing symptom in mBC, making it a patient-centered target for electronic PRO monitoring. Objective To determine whether digital PRO monitoring with alert-based responses reduces fatigue in patients with mBC. Design, Setting, and Participants This multicenter randomized clinical trial was conducted from May 2021 to February 2024, with 12 months of follow-up, at 52 breast cancer centers in Germany and included women aged 18 years or older with mBC who were receiving systemic therapy at any point in the metastatic disease course, had a life expectancy of longer than 3 months, were able to read German, and had smartphone access. Data analysis started in February 2024 and lasted 6 months. Interventions The intervention group completed weekly PRO questionnaires via a smartphone using validated short forms from the European Organization for Research and Treatment of Cancer computerized adaptive testing core item bank. Automated alerts based on predefined PRO deterioration were emailed to trained local nurses or physicians, who contacted patients by telephone within 48 hours. The control group received usual care with quarterly PRO questionnaires and no alerts. Main Outcomes and Measures The primary outcome was fatigue at 6 months. Secondary outcomes included fatigue, physical functioning, and quality of life over 12 months. PROs were reported as standardized T scores. Results Of 2008 patients screened, 924 (46.0%) were randomized, and 909 (45.3%) were included in the primary analysis (median age, 50 years [range, 19-83 years]). Baseline mean (SD) fatigue T scores were 57.6 (9.5) in the intervention group and 60.2 (9.0) in the control group ( P  < .001), with baseline PROs assessed after randomization but before group-specific follow-up began. At 6 months, adjusted mean fatigue was 54.5 (95% CI, 53.7- 55.4) vs 59.9 (95% CI, 59.0-60.8), yielding a mean difference of −5.4 points (95% CI, −6.6 to −4.1; P  < .001), exceeding the minimal clinically important difference (MCID) of 3.3 points. At 6 months, physical functioning was higher in the intervention group (mean difference, 4.0; 95% CI, 2.6-5.4), exceeding its MCID (3.2), whereas the between-group difference in quality of life was 0.8 points (95% CI, 0.02-1.5), which was less than the MCID of 2.9. Conclusions and Relevance This randomized clinical trial found that digital PRO monitoring was associated with clinically meaningful reductions in fatigue and improved physical functioning. These findings support further evaluation of alert-based PRO monitoring in routine oncology care. Trial Registration German Clinical Trials Register: DRKS00024015