Prostate cancer remains a significant global health burden, particularly in its metastatic forms (1). Synchronous oligometastatic prostate cancer (OMPC), defined as five or fewer metastatic lesions (typically lymph nodes or bones) at initial diagnosis, represents an intermediate state between localized and widely metastatic disease, offering an opportunity for aggressive local therapy (2). The advent of advanced imaging tools, such as prostate-specific membrane antigen positron emission tomography (PSMA-PET), has enhanced the detection of OMPC (3). Current standard care includes systemic therapies such as androgen-deprivation therapy (ADT) combined with androgen receptor pathway inhibitors (ARPIs), with or without docetaxel; however, disease progression remains a challenge (4–8). Robust evidence supports prostate-directed radiotherapy (PDRT) in hormone-sensitive OMPC, with trials such as HORRAD (9, 10) and STAMPEDE (11, 12) demonstrating survival benefits for PDRT combined with ADT in low-burden disease.

Despite these advances, untreated metastatic lesions often contribute to disease progression. Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) has gained recognition as an effective treatment for oligometastatic disease, delivering high doses of radiation to metastatic lesions with precision while minimizing damage to surrounding tissues (13). Simultaneous stereotactic total ablative radiotherapy (STAR) targeting both the prostate and metastases may further improve outcomes, yet data specific to synchronous OMPC are limited. A key challenge with STAR is the potential for increased treatment-related toxicity when concurrently irradiating multiple targets. Magnetic resonance-guided STAR (MRgSTAR), utilizing the superior soft-tissue contrast and real-time adaptation capabilities of MR-integrated linear accelerators (MR-LINACs), offers a promising approach to address these issues (14). This technology enables precise targeting and toxicity reduction across multiple treatment sites (15–18).

This study assessed the feasibility, toxicity, and preliminary clinical outcomes of MRgSTAR for synchronous OMPC, targeting both the prostate and pelvic metastatic lesions using a 1.5T MR-LINAC. By addressing unmet needs in local control, toxicity minimization, and survival improvement, this research aims to contribute to the evolving management of OMPC and provide a basis for future large-scale studies.

Between June 2020 and December 2023, 67 patients with PSMA-PET-diagnosed metastatic prostate cancer underwent 1.5T MR-guided SBRT at our institution. After excluding 24 patients with > 5 metastases, oligo-recurrent/progressive/resistant prostate cancer, prior prostatectomy, mCRPC, or follow-up < 3 months, 43 patients with synchronous OMPC were included ( Table 1 ).

All patients completed MRgSTAR, targeting 43 prostates, 88 lymph nodes, and 24 bone lesions. Most patients (65.1%; 28/43) had ≥ 2 metastatic targets, with 16.3% (7/43) having five. ATP and ATS were used in 168 (78%) and 47 (22%) fractions, respectively, with a median fraction duration of 60 minutes (range: 27–220 minutes). Extra-pelvic metastases in 12 patients were separately treated with SBRT prior to MRgSTAR. Among these 12 patients, extra-pelvic metastatic nodes (n = 6) and extra-pelvic bone metastases (n = 21) were irradiated using a LINAC (n = 7), helical tomotherapy (n = 1), and CyberKnife (n = 7). ADT combined with ARPI therapy was administered in 22 patients (52%).

The median follow-up duration was 36.5 months (range: 15.4–57.6 months). Three patients had biochemical progression at 9, 14, and 36 months post-MRgSTAR, with two having out-of-field progression and one having local progression as confirmed using PSMA-PET at 10, 14, and 36 months. In 13 patients who were assessed via follow-up PSMA-PET, no local persistence/progression in treated lesions was noted. All patients remained alive at the last follow-up, yielding a 3-year OS rate of 100%. The rates of bPFS, rPFS, and PFS were identically 95.2% (95% CI: 89.0%–100%) ( Figure 2 ).

Regarding MRgSTAR-related genitourinary (GU) and gastrointestinal (GI) toxicities, 9.3% (4/43) of patients experienced four acute grade 2 GU adverse events (AEs) within 3 months, all of which subsequently resolved. No subacute or late GU AEs of grade ≥ 2 were reported. Two patients (2/43, 4.7%) experienced subacute grade 2 GI AEs (rectal hemorrhage). One patient with an acute grade 2 GU AE also exhibited an acute grade 2 elevation in alanine aminotransferase, potentially unrelated to MRgSTAR. Additionally, 9.3% (4/43) of patients experienced late grade 2 non-GI/GU AEs. One patient (2.3%) developed subacute grade 3 neutropenia 4 months post-MRgSTAR, likely associated with ARPI use. Table 2 lists the details of AEs.

The log-rank test revealed no significant differences in rates of rPFS, bPFS, PFS, and OS, or toxicity across stratification factors (including clinical T stage, Gleason score, pre-radiotherapy PSA level, number of metastatic lesions, presence of bone or distant metastasis, ARPI use, and 1-month post-radiotherapy PSA level; Supplementary Table A2 ). However, these results should be interpreted with caution due to a limited number of events and a small sample size.

This study represents the first prospective evaluation of MRgSTAR for the simultaneous treatment of the prostate and pelvic oligometastatic lesions in patients with synchronous OMPC. Our results demonstrated that MRgSTAR offers low toxicity and promising early survival outcomes, potentially serving as a feasible and novel therapeutic strategy for synchronous OMPC.

Standard management of synchronous OMPC typically involves PDRT combined with ADT, as supported by the STAMPEDE (12) and HORRAD (9, 10) trials, which reported the survival benefits of the combination therapy over ADT alone. However, these trials did not address oligometastatic lesions, potentially leaving reservoirs for disease progression. In contrast, MRgSTAR targets both the prostate and metastases, offering a comprehensive approach to local control. With a median follow-up of 36.5 months, our cohort achieved a 3-year OS rate of 100% and PFS rate of 95.2% (95% CI: 89.0–100%). These outcomes appeared to be more favorable than data reported in STAMPEDE (3-year OS rate in low-burden metastatic patients: 81%) and HORRAD (median OS: ~45 months) (9, 10, 12). The enhanced survival outcomes in our study may be attributed to the ability of MRgSTAR (augmented by precise PSMA-PET staging) to aggressively target all detectable disease sites. However, direct comparisons are confounded by differences in imaging modalities (PSMA-PET versus conventional imaging) and systemic therapy regimens (ADT ± ARPI therapy versus ADT alone).

The role of metastasis-directed radiotherapy (MDRT) is well-established in metachronous OMPC, with trials such as ORIOLE (19) and STOMP (20) demonstrating the benefits of SABR in prolonging PFS and delaying initiation of systemic therapy. The application of MDRT in synchronous OMPC, however, remains less defined (21, 22). Siva et al. (23) reported that total metastatic ablation improved OS and PFS in patients with oligometastatic disease, including a subset with synchronous prostate cancer, supporting a broader use of MDRT. Similarly, the EXTEND study (24) demonstrated that MDRT, combined with intermittent hormone therapy, delayed time to progression in patients with OMPC, reinforcing the potential role of MDRT in altering the disease trajectory. Our study extended the MDRT paradigm to synchronous OMPC and suggested that simultaneous treatment of all lesions using MRgSTAR may similarly disrupt disease progression by eliminating metastatic subclones. Given their distinct biological and clinical profiles, synchronous and metachronous OMPC may require tailored therapeutic approaches. Our findings on MRgSTAR targeting all lesions implied the potential benefits of MDRT for patients with synchronous OMPC, shedding some light on the evolving therapeutic framework for this patient population.

Systemic therapy intensification with ARPI therapy alongside ADT is a cornerstone of metastatic castration-sensitive prostate cancer (mCSPC) management, with trials such as TITAN reporting a 3-year PFS rate of ~80% in low-volume disease (6). The better outcome in our study (3-year PFS rate: 95.2%) may be attributed to the strength of MRgSTAR to achieve precise local control. Notably, we observed that ARPI use and survival outcomes had no significant association, but a small sample size (n = 43) and a low number of progression events (n = 3) were the major limitations. Given the demonstrated efficacy of ARPIs in low-volume mCSPC and the capability of MRgSTAR to target macrometastases, the combination of these treatment modalities, along with ADT, is worth considering. Nonetheless, the effectiveness of MRgSTAR in local control may reduce the necessity for systemic therapy intensification or indicate a potential for treatment de-escalation in certain patients. This hypothesis should be validated in further trials.

MRgSTAR demonstrated a favorable toxicity profile in our cohort of patients with synchronous OMPC, of whom 9.3% and 4.7% having acute grade 2 GU toxicity and subacute grade 2 GI toxicity, respectively. No late grade ≥ 2 GU or GI toxicities were reported. These findings were more favorable than outcomes reported in studies utilizing conventional non-MRI–guided radiotherapy techniques. Montero et al. (25), Reverberi et al. (26), Imber et al. (27), and Deantoni et al. (28) conducted studies using conventional radiotherapy, SBRT, or intensity-modulated radiation therapy on 25–50 patients with follow-up periods ranging from 18–30 months. Of the participants across these studies, 15–20% had acute grade 2 GU toxicity, 5% had acute grade 3 GU toxicity [only reported in Reverberi et al. (26)], 8–15% had late grade 2 GU toxicity, 10–15% had acute grade 2 GI toxicity, and 4–8% had late grade 2 GI toxicity. Ingrosso et al. (29) reported that patients treated with volumetric image-guided moderately hypofractionated radiotherapy with daily cone-beam CT for localized prostate cancer had very low rates of late grade ≥ 3 GU (1.6%) and GI toxicities (0.9%). The lower rates of toxicities reported in our study may be associated with MRI guidance that facilitated precise radiation to target tumors and reduced irradiation to normal structures. These outcomes suggest that, with a favorable toxicity profile, MRgSTAR may serve as a promising approach to total ablative radiotherapy in OMPC.

Despite demonstrating the strengths of MRgSTAR, this study had several limitations. First, the small sample size and short follow-up duration precluded definitive conclusions about long-term efficacy and late toxicities of MRgSTAR. Second, due to the absence of a concurrent control group, we could only compare our data with historical cohorts in literature, restricting the generalizability of our findings. Third, the use of PSMA-PET for staging, although highly sensitive, may have introduced selection bias, potentially compromising the representativeness of the study cohort. Fourth, our outcomes may have been confounded by the heterogeneity of the patient cohort due to the inclusion of a subgroup with ARPI use, whereas we analyzed the outcomes stratified by treatment type to address this caveat, with the aim of clarifying the specific contributions of MRgSTAR. Moreover, in real-life clinical practice, the adoption of MRgSTAR remains narrow due to barriers including the limited availability of MR-LINACs and technical challenges such as extended treatment durations.

Several ongoing studies are investigating the combination of PDRT and MDRT for the treatment of synchronous OMPC. The CORE trial (NCT02759783) is a randomized study that compares standard systemic therapy alone versus systemic therapy combined with SABR in patients with prostate cancer and 1–3 oligometastatic lesions. Additionally, the STAMPEDE2 trial (NCT06320067) in the United Kingdom is examining the efficacy of intensified local and systemic therapies, including MDRT, in men with de novo metastatic prostate cancer and those with synchronous OMPC. These studies are designed to provide high-level evidence to inform the integration of MDRT into the treatment paradigm for OMPC, which is expected to validate or refine our study findings.

The highly promising results of our study indicate a substantial potential for integrating MRgSTAR into the management of OMPC. The outcomes of MRgSTAR should be further validated in larger trials. To expand its adoption, access to MR-LINACs should be enhanced. Despite these limitations, our research underscores the possibility of MRgSTAR as a more effective and precise radiotherapy method to improve clinical outcomes in patients with OMPC.