Postoperative Radiation Therapy and Controversies Regarding Hormonal Therapy in the Management of Prostate Cancer

Abstract

Biochemical recurrence (BCR) after radical prostatectomy (RP) remains a clinical challenge, with significant heterogeneity in outcomes and optimal management strategies. Salvage radiotherapy (sRT) is the standard approach, yet the role and duration of concurrent hormonal therapy (ADT) are still debated. Four key randomized controlled trials—RTOG 9601, GETUG-AFU 16, RTOG 0534 SPPORT, and RADICALS-HD—have explored the addition of ADT to sRT. While ADT consistently improved progression-free survival metastasis-free survival (MFS) benefit was not consistently observed, and overall survival (OS) gains were limited and primarily confined to patients with higher pre-sRT PSA levels (>0.6-0.7 ng/mL). Toxicity associated with long-term ADT, including metabolic and cardiovascular effects, underscores the importance of patient selection. Emerging tools such as PSMA PET/CT and the Decipher genomic classifier show promise in refining risk stratification. PSMA PET/CT can identify occult metastases and guide treatment planning, while Decipher can help predict who may benefit from ADT. Retrospective and prospective data support their integration into clinical practice. Recent trials evaluating intensified systemic therapy with androgen receptor pathway inhibitors (ARPIs) in combination with sRT suggest potential benefit in high-risk BCR populations, although added toxicity remains a concern. The optimal role and timing of ARPIs in the early salvage setting require further investigation. In conclusion, the decision to add ADT to sRT in BCR patients should be individualized based on PSA kinetics, imaging, and genomic profiling. Shared decision-making and future biomarker-driven trials will be key to personalizing therapy and improving outcomes while minimizing harm.