What is the recommended duration of Androgen Deprivation Therapy (ADT) for patients with Biochemical Recurrence (BCR) after Radical Prostatectomy (RP) who are candidates for salvage Radiation Therapy (RT)?

Duration of ADT After BCR in RP Patients Receiving Salvage RT

For patients with high-risk features undergoing salvage RT after radical prostatectomy, ADT should be administered for a minimum of 4-6 months, with strong consideration for extending to 18-24 months in those with the most aggressive disease characteristics. 1

Minimum Duration: 4-6 Months

The 2024 AUA/ASTRO/SUO guidelines establish 4-6 months as the minimum duration of ADT when combined with salvage RT for patients with any high-risk features. 1 This recommendation is based on three landmark randomized trials (GETUG-AFU 16, RTOG 9601, and NRG/RTOG 0534 SPPORT) that demonstrated 40-60% improvement in freedom from clinical progression with ADT durations ranging from 4-6 months at minimum. 1

• ADT can be initiated either concurrently with salvage RT or up to 2 months prior to starting radiation, based on trial protocols. 1
• Shorter durations than 4 months have not been demonstrated to improve patient outcomes. 1
• All three trials showed survival advantages with concurrent ADT, with RTOG 9601 and NRG/RTOG 0534 SPPORT specifically demonstrating overall survival benefits. 1

Extended Duration: 18-24 Months for High-Risk Disease

For patients with high-risk features, clinicians may extend ADT duration to 18-24 months. 1 This expert opinion recommendation is particularly relevant for patients with:

• Grade Group 4-5 (Gleason score 8-10) 1
• Positive surgical margins 1
• Higher PSA at time of salvage RT (≥0.7 ng/mL) 1
• PSA doubling time ≤6 months 1
• Seminal vesicle involvement (pT3b-4) 1
• Persistently detectable post-operative PSA 1

Evidence Supporting Extended Duration

Stratified analysis from RTOG 9601, which used 24 months of high-dose bicalutamide, demonstrated that longer-term ADT was associated with lower likelihood of progression and death specifically in patients with high-risk factors. 1 The trial included 18% of patients with Grade Group 4-5 cancer and 70% with high-risk features, showing particular benefit in this population. 1

Retrospective data from 680 patients receiving post-RP RT found that patients receiving <12 months of ADT had significantly increased biochemical failure (HR: 2.27) and distant metastasis (HR: 2.48) compared to those receiving ≥12 months. 2 Each additional month of ADT was associated with decreased risk for biochemical failure (HR: 0.95), distant metastasis (HR: 0.88), and prostate cancer-specific mortality (HR: 0.90). 2

Clinical Decision Algorithm

Step 1: Identify High-Risk Features

Determine if the patient has ANY of the following: 1

• PSA ≥0.7 ng/mL at time of BCR
• Grade Group 4-5
• PSADT ≤6 months
• Persistently detectable post-operative PSA
• Seminal vesicle involvement (pT3b-4)
• Node-positive disease

Step 2: Determine ADT Duration

• If NO high-risk features present: Consider salvage RT alone (ADT optional). 1
• If ANY high-risk features present: Offer ADT with salvage RT for minimum 4-6 months. 1
• If MULTIPLE high-risk features or Grade Group 4-5: Extend ADT to 18-24 months. 1

Step 3: Timing of Initiation

Start ADT either concurrently with salvage RT or up to 2 months prior to radiation initiation. 1

Important Caveats

PSA threshold considerations: For patients with PSA <0.7 ng/mL, PSA alone should not determine ADT use—other high-risk features must be considered. 1 The NRG/RTOG 0534 SPPORT trial suggests a potential alternative threshold of 0.35 ng/mL, though this comes from underpowered secondary analysis. 1

Margin status caveat: While positive surgical margins are listed as a high-risk feature, this is one of the more inconsistent risk indicators for ADT benefit. 1 Subgroup analyses from the three major trials showed conflicting results regarding margin status. 1

Awaiting definitive data: The ongoing RADICALS-HD trial (NCT00541047) is directly comparing short-term versus long-term ADT with salvage RT and will provide more definitive guidance on optimal duration. 1 Until these data mature, the 18-24 month recommendation for high-risk patients remains expert opinion. 1

Toxicity considerations: ADT increases acute grade 2 adverse events, hot flashes, hypertension, gynecomastia, and sexual dysfunction. 1 However, these quality-of-life impacts must be weighed against the mortality and metastasis benefits, particularly in high-risk patients where longer ADT durations showed reduced distant metastasis rates (6.0% vs 23% at 5 years for ≥12 vs <12 months). 2