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What are current first-line treatments for biochemical recurrence after radical prostatectomy?
Executive summary
Current first-line approaches to biochemical recurrence (BCR) after radical prostatectomy (RP) center on risk-directed evaluation with PSMA-PET imaging and early salvage radiotherapy (sRT) to the prostate bed for most patients; systemic therapy (androgen-deprivation therapy [ADT] alone or ADT combined with androgen receptor signaling inhibitors [ARSIs]) is recommended or considered for high‑risk or PSMA‑positive cases [1] [2] [3]. Consensus panels and recent meta-analyses emphasize tailoring treatment by PSA kinetics, pathologic grade, and imaging findings because low‑risk patients may be observed while high‑risk patients often need combined local and systemic intensification [4] [5].
1. A diagnostics-first principle: image before you intensify
Guidelines and consensus discussions now prioritize restaging with PSMA‑PET for patients with BCR after RP because modern imaging often changes intended management—distinguishing local-only from regional or distant disease is essential to choosing sRT versus systemic therapy or metastasis‑directed approaches [6] [4] [7]. APCCC and guideline authors argue that imaging yield and the clinical implications (curative intent vs. disease control) depend on PSA doubling time, grade group and time to failure, so clinicians should use those predictors to optimize when and which scans to order [4] [2].
2. Early salvage radiotherapy is the default local-first option
Multiple reviews and recent practice updates state that early sRT to the prostate bed is preferred over routine immediate adjuvant radiotherapy after RP in patients monitored closely, because sRT provides comparable or superior outcomes when applied early at biochemical recurrence and is associated with improved biochemical‑control and prostate‑cancer specific outcomes in pooled analyses [1] [8]. Observational and pooled data also show better results when pre‑sRT PSA is lower, supporting early referral for radiation planning once recurrence is confirmed [8].
3. Risk stratification determines when to add systemic therapy
High‑risk BCR—commonly defined as PSA doubling time ≤1 year, ISUP grade group 4–5, or recurrence ≤18 months—signals a substantial chance of micrometastatic disease and worse outcomes; in that setting, salvage radiotherapy alone may be insufficient and clinicians consider combining sRT with ADT or systemic intensification [3] [4] [9]. Network meta-analyses and reviews suggest that for high‑risk or post‑RT recurrences, ADT plus an ARSI may be appropriate, indicating a shift toward earlier systemic intensification for selected patients [5] [10].
4. What “systemic intensification” looks like today
Systemic options cited in contemporary reports include short‑term or longer ADT added to sRT, and emerging evidence/ongoing trials examine the benefit of adding ARSIs (enzalutamide, apalutamide, darolutamide) to ADT in high‑risk BCR; the ARASTEP and other phase III programs are examples of trials testing darolutamide or other ARSIs with ADT in this setting [10] [9] [5]. Reviews also reference that when PSMA‑PET shows clear metastatic disease and aggressive features, clinicians may follow non‑metastatic or metastatic castration‑sensitive prostate cancer (nmCSPC/mCSPC) paradigms for systemic treatment [2].
5. Surveillance and metastasis‑directed therapy for select patients
For low‑risk BCR (longer PSA‑DT, lower grade), observation or surveillance remains an acceptable first‑line approach with close PSA monitoring, reserving sRT or systemic therapy until clear progression or imaging‑detectable disease; metastasis‑directed therapy (MDT) such as stereotactic radiotherapy to limited PSMA‑positive lesions is an evolving option for oligometastatic presentations and has altered management in trials and practice [8] [11] [7].
6. Evidence gaps, controversies and ongoing trials
Randomized data guide some decisions (e.g., timing of sRT vs adjuvant RT) but questions remain about optimal ADT duration with sRT, which patients truly benefit from adding ARSIs, and how best to integrate ultra‑sensitive PSA thresholds and next‑generation imaging into decision algorithms; systematic reviews call for individualized care and note heterogeneous evidence across studies [5] [1]. Several ongoing phase III trials (including ARSI combinations) are explicitly testing systemic intensification strategies in high‑risk BCR and will clarify practice in coming years [10] [5].
7. Practical takeaways for clinicians and patients
Begin with risk assessment (PSA‑DT, pathologic grade, time since RP), restage with PSMA‑PET when indicated, offer early salvage prostate‑bed RT for most patients with detectable PSA after RP, and add ADT or consider ADT+ARSI for those meeting high‑risk criteria or with PSMA‑positive metastatic disease; low‑risk patients may undergo surveillance [4] [1] [2]. Available sources do not mention specific, universally agreed ADT durations or a single ARSI regimen that is standard for all high‑risk BCR—those details are being defined by ongoing trials [5] [10].