What is the ideal duration of Androgen Deprivation Therapy (ADT)?

Ideal Duration of Androgen Deprivation Therapy (ADT)

Risk-Stratified Duration Recommendations

The optimal duration of ADT depends entirely on disease risk category and treatment context, with high-risk localized disease requiring at least 24 months, intermediate-risk disease requiring 6 months when combined with radiotherapy, and metastatic disease requiring continuous therapy. 1

For Localized Disease with Radiotherapy

Intermediate-Risk Disease:

• ADT should be administered for 6 months when combined with moderate-dose radiotherapy (<70 Gy) 1
• This represents Level I evidence with Grade A recommendation strength 1

High-Risk and Locally Advanced Disease (≥T2b):

• ADT must be continued for at least 24 months (24-36 months total) when combined with radiotherapy 1, 2
• Evidence demonstrates that long-term ADT (24-36 months) is superior to short-term ADT (4-6 months) in this population 1
• There is no evidence that extending ADT beyond 24-36 months provides additional benefit 1
• This represents Level I evidence with Grade A recommendation strength 1
• RTOG 92-02 specifically showed superior outcomes with 2+ years versus 4 months of ADT in high-risk patients, with particular benefit in Gleason 8-10 disease (overall survival 45% vs 32%, P=0.0061) 2

Very High-Risk Disease (T3b-T4):

• Long-term ADT for 2-3 years is recommended when combined with definitive radiation 2
• EORTC 22961 confirmed superior survival when 2.5 years of ADT was added to radiotherapy in T2c-T3 disease 2

For Post-Prostatectomy Settings

Adjuvant or Salvage Radiotherapy:

• Additional hormone therapy with adjuvant or salvage radiotherapy following prostatectomy is NOT recommended as standard care 1
• This carries Level V evidence with Grade D recommendation strength 1
• The RTOG 96-01 trial showed that 24 months of bicalutamide with salvage radiotherapy improved freedom from PSA progression (57% vs 40%, P<0.0001) and reduced metastasis incidence (7.4% vs 12.6%, P<0.04), but definitive results remain pending 1
• This remains investigational and should be considered only in carefully selected high-risk patients 1

For Biochemical Recurrence

PSA-Only Recurrence:

• Treatment timing should be guided by PSA doubling time (PSADT), absolute PSA level, and life expectancy 1
• Patients with PSADT >12 months who are older are candidates for observation rather than immediate ADT 1
• Patients with shorter PSADT (<12 months) and long life expectancy should be encouraged to consider ADT earlier 1
• When ADT is initiated for biochemical recurrence, intermittent ADT should be considered over continuous therapy 1
• The PR.7 trial demonstrated that intermittent ADT was noninferior to continuous ADT for overall survival (8.8 vs 9.1 years, HR 1.02), with better quality of life including improved physical function, reduced fatigue, fewer urinary problems, less severe hot flashes, and better libido and erectile function 1

For Metastatic Disease

Hormone-Naïve Metastatic Disease:

• Continuous ADT is the gold standard and should be maintained throughout the disease course 1, 3
• Castrate levels of testosterone must be maintained even when the disease progresses to castration-resistant prostate cancer (CRPC), as the androgen receptor remains active 1, 3
• The SWOG 9346 trial comparing intermittent to continuous ADT in metastatic patients was statistically inconclusive for noninferiority (HR 1.10,90% CI 0.99-1.23), and a 20% greater mortality risk with intermittent therapy cannot be ruled out 1
• Quality of life measures for erectile function and mental health were better with intermittent ADT at 3 months off treatment, but differences became insignificant thereafter 1

When Continuous ADT Should Be Maintained:

• ADT should continue as long as the patient has reasonable life expectancy where disease control matters for quality of life 3
• Even with PSA progression or isolated disease site progression, ADT should be maintained if the patient is tolerating treatment and experiencing overall disease control 3
• When additional systemic therapies are added for treatment intensification, continuous ADT remains the backbone of treatment 3

Critical Caveats and Common Pitfalls

Cardiovascular Considerations:

• In patients with pre-existing cardiovascular morbidity, long-term LHRH analogs should be used with caution due to increased cardiovascular mortality risk 1
• In these patients, bicalutamide 150 mg can be considered as an alternative based on the EPC trial results 1

Monitoring Requirements for Intermittent ADT:

• Close monitoring of PSA and testosterone levels, and possibly imaging, is required during off-treatment periods 1
• Patients may need to switch to continuous ADT upon signs of disease progression 1

Common Errors to Avoid:

• Do not discontinue ADT based solely on PSA progression without considering overall clinical benefit 3
• Do not stop therapy at an arbitrary timepoint without evaluating continued clinical benefit 3
• Do not fail to distinguish between isolated progression in limited disease sites versus global disease progression 3
• Do not overlook the need for continued testosterone suppression even when adding other systemic therapies 3

Side Effect Management:

• Side effects of continuous ADT are cumulative over time and include hot flashes, weight gain, loss of libido, erectile dysfunction, osteoporosis, metabolic syndrome, and cardiovascular risk 1, 2
• Bone density screening, calcium/vitamin D supplementation, lipid profile monitoring, glucose monitoring, and cardiovascular risk factor assessment should be performed regularly 2
• Depression, anxiety, and body image concerns are common and should be screened 2

Emerging Evidence

A 2018 randomized trial comparing 36 months versus 18 months of ADT combined with radiotherapy in high-risk prostate cancer showed no survival difference (5-year OS 91% vs 86%, p=0.07), with the 18-month group experiencing better quality of life 4. However, this single study has not yet changed guideline recommendations, which continue to recommend 24-36 months based on the totality of evidence 1, 2.