Is early androgen deprivation therapy (ADT) beneficial for patients with biochemical Prostate-Specific Antigen (PSA) relapse after radical prostatectomy followed by radiotherapy?

Early ADT Does Not Improve Overall Survival in Biochemical PSA Relapse After Radical Prostatectomy Followed by Radiotherapy

Early androgen deprivation therapy (ADT) is not routinely recommended for patients with biochemical PSA relapse after radical prostatectomy followed by radiotherapy, as the available evidence does not demonstrate an overall survival benefit. Multiple high-quality guidelines consistently recommend against routine early ADT in this clinical scenario unless specific high-risk features are present 1.

Evidence Against Routine Early ADT

The most authoritative guidelines from ESMO (European Society for Medical Oncology) explicitly state that hormonal therapy is not routinely recommended for men with prostate cancer who have biochemical relapse unless they have symptomatic local disease progression, proven metastases, or PSA doubling time <3 months 1. This recommendation is based on Level I evidence showing no overall survival benefit from early ADT 1.

Key Supporting Data

• Retrospective series evaluating ADT for relapse following radical prostatectomy or radiotherapy observed no survival benefit, although time to clinical metastases was delayed by early androgen treatment 1.

• The landmark PR.7 trial (1386 patients) comparing intermittent versus continuous ADT in biochemical relapse showed median overall survival of 8.8 versus 9.1 years respectively (HR 1.02; 95% CI 0.86-1.21), demonstrating no survival advantage for ADT initiation 1.

• A large observational study from CaPSURE emulating a randomized trial found that immediate ADT within 3 months of PSA relapse had similar survival to deferred ADT (adjusted HR 0.91; 95% CI 0.52-1.60), with 5-year survival difference of only -2.0% 2.

Clinical Context: The Sequence Matters

The question specifically addresses patients who have already received both radical prostatectomy AND radiotherapy. This is a critical distinction because:

• Salvage radiotherapy is the primary recommended intervention for PSA recurrence after prostatectomy 3, ideally initiated at PSA <0.5 ng/mL 1, 3.

• If patients have already failed both surgery and radiotherapy, they are in a different clinical scenario than those with PSA relapse after prostatectomy alone.

• The NCCN guidelines note that most patients with biochemical failure will have a good 15-year prognosis, with outcomes best approximated by absolute PSA level, PSA doubling time, and initial disease characteristics 1.

When to Consider ADT in This Population

ADT should be considered selectively based on specific high-risk features rather than routinely initiated 1:

High-Risk Indicators for Earlier ADT Consideration:

• PSA doubling time <3 months 1
• PSA doubling time <6-12 months with long life expectancy 1
• Symptomatic local disease progression 1
• Proven metastatic disease 1
• Baseline PSA >50 ng/mL 1

Observation is Appropriate For:

• Men with prolonged PSA doubling times (>12 months), especially if older 1
• Low-volume, low-risk disease (PSA <1.0, Gleason score <7, PSA doubling time >15 months) 1

Quality of Life Considerations

When ADT is initiated in this setting, intermittent ADT is recommended over continuous ADT based on Level I evidence 1:

• The PR.7 trial demonstrated that intermittent ADT was non-inferior to continuous ADT for overall survival while providing superior quality of life in multiple domains including physical function, fatigue, urinary problems, hot flashes, libido, and erectile dysfunction 1.

• Many side effects of continuous ADT are cumulative over time, making intermittent therapy particularly attractive when ADT is used for biochemical recurrence 1.

Common Pitfalls to Avoid

Do not initiate ADT reflexively based solely on rising PSA after both prostatectomy and radiotherapy have been completed. The evidence shows:

• Early ADT delays time to metastases but does not improve overall survival 1.
• Patient anxiety about rising PSA should not drive treatment decisions 1.
• The cumulative toxicity of ADT significantly impacts quality of life without survival benefit in most patients 1.

Special Consideration: Recent FDA Approval

The FDA recently approved enzalutamide for non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis 4. However, this represents a newer treatment paradigm and the question specifically asks about "early ADT" in the traditional sense. This approval does not change the fundamental recommendation that routine early ADT lacks overall survival benefit in unselected patients with biochemical recurrence 1.

Clinical Algorithm

For patients with biochemical PSA relapse after radical prostatectomy followed by radiotherapy:

1. Assess PSA kinetics: Calculate PSA doubling time
2. Evaluate for metastatic disease: Imaging if PSA >10 ng/mL or rapid PSA kinetics 3
3. Risk stratify:
   • Low risk (PSA doubling time >12 months, older age): Observation 1
   • Intermediate risk (PSA doubling time 3-12 months): Close monitoring, consider ADT discussion
   • High risk (PSA doubling time <3 months, symptomatic disease, or metastases): Consider ADT 1
4. If ADT initiated: Use intermittent rather than continuous therapy 1

The weight of guideline evidence clearly indicates that early ADT does not provide overall survival benefit in this population and should be reserved for patients with high-risk features 1.