When should androgen‑deprivation therapy be added to salvage radiotherapy after prostatectomy?
Executive summary
Androgen‑deprivation therapy (ADT) should be added to salvage radiotherapy (SRT) after radical prostatectomy when biochemical recurrence (BCR) is accompanied by high‑risk features—most guidelines and randomized trials support combined therapy in that setting because it improves metastasis‑free outcomes compared with SRT alone [1] [2]. The exact PSA threshold and optimal ADT duration remain areas of evolving evidence: major trials show benefit for short‑term ADT and at least one large trial favors long‑term ADT for better metastasis‑free survival, so decisions must balance disease risk, side effects, and patient priorities [2] [3] [4].
1. Why the question matters now: trials, guidelines and shifting thresholds
Multiple randomized trials (RTOG 9601, GETUG‑AFU 16, NRG/RTOG 0534 SPPORT) established that adding hormone therapy to SRT reduces metastatic progression versus SRT alone, and those data underpin contemporary guideline recommendations to “offer ADT” for patients with BCR and high‑risk features after prostatectomy [5] [2] [6] [1]. Newer, large randomized data from RADICALS‑HD extend the debate to duration of ADT, showing longer exposure produced a metastasis‑free survival benefit in certain comparisons, which has sharpened guideline attention to when and how long to treat [4] [3].
2. Who is “high‑risk” and therefore should be offered ADT with SRT
Guideline panels recommend offering ADT in addition to salvage RT for patients with BCR after radical prostatectomy who have any high‑risk features—examples explicitly cited include higher presalvage PSA (commonly ≥0.7 ng/mL), Gleason Grade Group 4–5, PSA doubling time ≤6 months, persistently detectable postoperative PSA, seminal vesicle invasion, or other adverse pathology and imaging/genomic indicators [1] [6]. Analyses of RTOG and contemporary trials inform the PSA threshold language; RTOG 9601 data support the ≥0.7 ng/mL threshold while SPPORT and secondary analyses suggest a lower threshold (≈0.35 ng/mL) might be reasonable in some circumstances, though that finding is less robust [1].
3. What the randomized data say about benefit and duration
GETUG‑AFU 16 demonstrated that short‑term ADT added to SRT improved metastasis‑free survival at long follow‑up, confirming the efficacy of combining therapy for men with rising PSA after prostatectomy [2] [7]. RTOG 9601 showed that hormone therapy plus SRT lowers rates of metastasis and death compared with SRT alone, providing a foundational proof‑of‑principle [5]. RADICALS‑HD later compared no ADT, 6‑month ADT, and 24‑month ADT in the post‑prostatectomy setting and reported that 24 months improved metastasis‑free survival versus 6 months, while 6 months did not significantly beat no ADT in that interim analysis—highlighting that longer ADT can improve disease control but also raises the tradeoffs of toxicity and quality‑of‑life impact [4] [3].
4. Harms, uncertainties and pragmatic counsel for clinicians
ADT carries well‑documented side effects and downstream impacts on cardiovascular risk, metabolism, bone health and quality of life, and older observational work cautioned about variable survival benefit across patient groups, so treatment must be individualized and informed by PSADT, pathologic features, genomic classifiers, and PET imaging when available [8] [1] [9]. Guideline language is pragmatic—“offer” ADT for high‑risk BCR rather than an absolute mandate—because thresholds and optimal duration are still evolving and different trials used different ADT regimens and patient selection [1] [4]. Trials do not support adding cytotoxic chemotherapy to SRT plus ADT in this setting [10].
5. Bottom line recommendation based on current evidence
For men with biochemical recurrence after prostatectomy who have high‑risk features (eg, presalvage PSA around or above 0.7 ng/mL, Gleason Grade Group 4–5, PSADT ≤6 months, persistent PSA, seminal vesicle or nodal involvement), clinicians should offer ADT in addition to salvage radiotherapy, discuss the probable benefits for metastasis‑free survival and the tradeoffs of toxicity, and individualize ADT duration—short‑term (≈6 months) is supported by GETUG‑AFU 16 while longer courses (eg, 24 months) improved metastasis‑free survival in RADICALS‑HD but increase exposure to harms [1] [2] [3] [4]. If patients lack high‑risk features, the benefit of routine ADT with SRT is less certain and deferred or no ADT can be reasonable while employing close surveillance and consideration of imaging/genomic risk tools [1] [9].