Prostate-specific antigen flare induced by ²²³RaCl₂ in patients with metastatic castration-resistant prostate cancer

Purpose: Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer, but its impact during radium-223 dichloride (²²³RaCl₂) therapy is still unclear. This radioisotope has shown to improve overall survival in metastatic castration-resistant prostate cancer (mCRPC). We sought to evaluate the impact of PSA flare on survival and its relation with metabolic parameters on ¹⁸F-labeled sodium fluoride PET/CT. Methods: We conducted a retrospective study of 168 patients with mCRPC (median age 69; median PSA 29.7) receiving ²²³RaCl₂. Overall survival (OS) and progression-free survival (PFS), estimated by the Kaplan–Meier method and compared using a log-rank test, were evaluated for patient groups corresponding to different definitions of PSA flare. Metabolic ¹⁸F-fluoride PET/CT data were analyzed as well. Results: Immediate PSA decline was observed in 49 patients (29.2%), whereas no PSA response was observed in 59 patients (35.1%). PSA flare (defined as rise after the first cycle followed by decrease below the baseline) was observed in 20 patients (11.9%) and PSA flare followed by a decrease from peak but not below baseline was observed in 40 (23.8%). The first flare subgroup had a median PFS and OS of 20.8 and 23.9 months, respectively. These outcomes were not significantly different from patients with immediate PSA decrease, but were significantly better than in patients with persistent PSA elevation (3.1 months for PFS and 11.5 months for OS, p < 0.001). Moreover, the PSA flare group showed an alkaline phosphatase (ALP) decrease significantly greater than non-responders (p = 0.003). Metabolic ¹⁸F-fluoride PET/CT data were available in 35 patients at baseline and during ²³³RaCl₂ therapy. The tumor burden reduction, expressed by ΔTLF₁₀ and ΔFTV_10, was more evident within PSA flare group below baseline than non-responders (p = 0.005 and 0.001, respectively). Conclusions: This report suggests that a flare does not necessarily indicate lack of response to ²²³RaCl₂ therapy.