Natural history and risk-stratification of biochemical recurrence in prostate cancer treated with definitive radiotherapy.

348 Background: Biochemical recurrence (BCR) of prostate cancer following radiation therapy often does not result in clinically significant events, but a subset of patients may be at higher risk of developing metastatic disease or death. Identifying these patients is critical for clinical decision making, but unlike in the post-prostatectomy setting, no method has been externally validated for BCR after radiation therapy. This study characterized outcomes after post-radiation BCR and validated a proposed risk stratification heuristic. Methods: This was a retrospective, multicenter, nationwide cohort study of patients having post-radiation BCR treated in the United States Veterans Administration Health System. High-risk post-radiation BCR was defined as either Gleason score ≥8 or BCR occurring within 18 months of radiation therapy. BCR was defined as post-treatment PSA greater or equal to PSA nadir + 2 ng/ml, initiation of androgen deprivation therapy distinct from the initial treatment course, or development of metastatic disease, whichever occurred first. Results: Median time to BCR was 42.5 months (interquartile range 22.9-73.0). Among 7,126 patients who experienced BCR, 35.5% of patients developed metastatic disease and 17.4% died of prostate cancer at 10 years. 38.5% of patients had at least one qualifying high-risk feature of whom 23.3% had high-risk recurrence based on time to recurrence alone, 57.6% based on Gleason/Grade Group alone, and 19.1% based on both criteria. High-risk BCR resulted in higher 5-year rates of metastatic disease (42.0% versus 24.5%, hazard ratio (HR) 1.83, 95% confidence interval (CI) 1.69-1.98, p < 0.001), death from prostate-cancer (18.7% versus 8.78%, HR 1.82, 95% CI 1.63-2.03, p < 0.001), and death from all causes (37.1% versus 30.8% rates, HR 1.18, 95% CI 1.11-1.26, p < 0.001). Conclusions: A simple, two-element risk stratification tool using existing clinically data is the first validated tool for identifying patients at risk of metastases or PCSM following post-radiation BCR. Most patients experiencing BCR in this context do not develop metastases or lethal prostate cancer, making such stratification essential for treatment decision-making and refinement of patient populations for clinical trials. Further work remains on risk-adapted therapy intensification.