Radiotherapy Results in Lower Risk of Distant Metastasis in High-Risk Prostate Cancer Compared With Radical Prostatectomy

A new analysis comparing radiotherapy (RT) with long-term androgen deprivation therapy (LT-ADT) and radical prostatectomy (RP) with selective postoperative RT with or without androgen deprivation therapy (ADT) suggests that RT-based strategies may result in a lower risk of distant metastasis (DM) in patients with high-risk prostate cancer (HR-PCa). The study, presented as an emulated randomized comparison, leverages individual patient data from two phase III randomized trials to minimize bias and provide a more robust evaluation of treatment outcomes. The results are presented by Soumyajit Roy, MD, of Rush University Medical Center, at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Standard treatment options for HR-PCa include RT with LT-ADT or RP, often followed by postoperative RT and ADT as needed. However, previous retrospective population-based and multicenter comparisons have produced mixed results with substantial bias, making it difficult to establish a definitive treatment strategy. To address these limitations, researchers conducted an emulated randomized comparison of data from patients included in two clinical trials that enrolled contemporaneously in the same country, ensuring more comparable patient populations.

The study included 1,290 patients, with 557 receiving RT and 733 undergoing RP. The median follow-up was 6.4 years, and inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics between the two groups. Before weighting adjustments, patients in the RP cohort were significantly younger and had lower baseline prostate-specific antigen levels than those in the RT group.

The primary endpoint was the cumulative incidence of DM, and deaths were considered as competing events. Researchers also evaluated death after DM to create a harmonized metric assessing prostate cancer–specific mortality. In addition, non–cancer-related deaths were analyzed to assess potential residual selection bias between the treatment groups.

Findings showed that the 8-year cumulative incidence of DM was significantly lower in the RT cohort compared with the RP cohort, with rates of 16% versus 23% (P=.01). The subdistribution hazard ratio (sHR) for DM favored RT (sHR, 0.48; 95% CI, 0.34-0.69; P<.001), indicating a nearly 50% reduction in risk compared with RP. Despite this advantage, the rate of death after DM was similar between the groups, with 10% in the RP cohort and 8% in the RT cohort (P=.72).

Patients who received RT had a significantly higher risk of death without DM (HR, 2.09; 95% CI, 1.01-4.34; P=.048), suggesting the possibility of residual confounding factors. Researchers noted that differences in patient selection and comorbidities could contribute to this finding, emphasizing the need for cautious interpretation.

A secondary analysis compared the standard-of-care RT+LT-ADT group with the cohort receiving RP with ADT and docetaxel. The 8-year cumulative incidence of DM was 18% for the RT+LT-ADT group versus 21% for the ADT+docetaxel+RP group (sHR, 0.75; 95% CI, 0.45-1.24; P=.26). This comparison suggests that the addition of systemic therapies to RP may help close the gap in DM rates between the two treatment approaches, although the difference was not statistically significant.

The study’s authors conclude that an RT-based strategy may be more effective in reducing DM in patients with HR-PCa enrolled in clinical trials. However, they acknowledge the limitations of their analysis, particularly the presence of residual selection bias despite use of cooperative group trial data and IPTW adjustments. As the authors state, “Longer follow-up is needed to assess deaths attributed to PCa. Despite the strengths of the comparison . . . there appears to be residual unmeasured bias, as expected, based on greater early deaths without DM in the RT arm.”