Purpose <p>To evaluate the safety, feasibility, and patient-reported outcomes of magnetic resonance-guided simultaneous multi-focal adaptive radiotherapy for the prostate, pelvis, and metastases (MRgSMART-PEM) in patients with high-risk, very-high-risk, or oligometastatic prostate cancer.</p> Methods and materials <p>In this prospective single-arm phase II study, 35 patients with pathologically confirmed prostate cancer (11 localized, 8 pelvic nodal, 16 oligometastatic) were treated with MRgSMART-PEM on a 1.5-T MR-Linac between June 2021 and March 2025. Radiotherapy was delivered in five alternate-day fractions using an Adapt-to-Shape workflow. The primary endpoint was clinician-reported acute grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicity within 12 weeks. Secondary endpoints included late toxicity, quality of life (QoL), and survival outcomes.</p> Results <p>Median follow-up was 17.2 months (range, 4.3–49.3). The median on-couch time was 59&#xa0;min (range, 35–80). Acute grade ≥ 2 GU and GI toxicities occurred in 5.7% of patients each, including one grade 3 GI event; all resolved within 8 weeks. No late grade ≥ 2 toxicities were observed, and no grade 1 events persisted beyond 18 months. QoL scores declined at 2 weeks post-treatment but returned to baseline by 3 months. At 2 years, biochemical and clinical progression-free survival rates were both 87.4%, and in-field control was 100%.</p> Conclusions <p>MRgSMART-PEM is feasible, safe, and well tolerated in patients with high-risk, very-high-risk, and oligometastatic prostate cancer, achieving excellent local control with minimal toxicity and recovery of QoL. These results support further evaluation of MRgSMART-PEM in randomized trials.</p> Trial registration <p>NCT05183074 (Chinese Academy of Medical Sciences, First Posted 2022-01-10).</p>