What is the protocol for administering intermittent Androgen Deprivation Therapy (ADT) to a patient with metastatic castrate-sensitive prostate cancer?

Intermittent ADT Protocol for Metastatic Castrate-Sensitive Prostate Cancer

Primary Recommendation

Continuous ADT remains the standard of care for metastatic castrate-sensitive prostate cancer, as intermittent ADT failed to demonstrate noninferiority for overall survival in this population. 1, 2 However, intermittent ADT may be considered in carefully selected patients who achieve adequate PSA suppression and are willing to accept potential survival uncertainty in exchange for quality-of-life benefits. 1, 3

Evidence Against Routine Use in Metastatic Disease

The SWOG 9346 trial specifically evaluated intermittent versus continuous ADT in 1,535 metastatic patients and found the results statistically inconclusive for noninferiority, with the hazard ratio for death (1.10,90% CI 0.99-1.23) exceeding the prespecified upper boundary of 1.20. 1 This means a 20% greater mortality risk with intermittent ADT cannot be ruled out. 1

• Median survival was 5.1 years with intermittent ADT versus 5.8 years with continuous ADT in the overall population. 1
• Post-hoc analysis revealed patients with minimal disease burden had worse outcomes with intermittent therapy (5.4 vs 6.9 years median survival, HR 1.19), while those with extensive disease showed similar outcomes (4.9 vs 4.4 years, HR 1.02). 1

When Intermittent ADT May Be Considered

If intermittent ADT is used despite the evidence favoring continuous therapy, it should only be offered to patients with extensive metastatic disease who achieve excellent PSA response and prioritize quality of life over potential survival benefit. 1, 3

The European Association of Urology notes that 94% of expert panelists would discuss intermittent ADT as an option specifically in metastatic patients achieving adequate PSA decline (below 4 ng/mL after 6 months of induction therapy). 3

Specific Protocol for Intermittent ADT Administration

Induction Phase

• Initiate standard ADT with LHRH agonist or antagonist (or bilateral orchiectomy). 1, 4
• For LHRH agonists specifically: Administer antiandrogen therapy starting at least 7 days before or coadministered with the LHRH agonist and continue for at least 7 days (or 3-4 weeks per some guidelines) to prevent testosterone flare in patients with overt metastases. 1, 4
• Continue ADT for 7 months as the induction period. 1

Criteria to Stop ADT (Off-Treatment Period)

• PSA must decrease to ≤4 ng/mL after the 7-month induction period, demonstrating androgen sensitivity. 1
• Only patients achieving this PSA threshold should proceed with intermittent cycles. 1

Off-Treatment Monitoring

• Close monitoring of PSA and testosterone levels, and possibly imaging, is required during off-treatment periods. 1, 2
• Monitor PSA regularly (typically monthly initially, then every 3 months). 1

Criteria to Restart ADT (On-Treatment Period)

• Reinitiate ADT when PSA reaches 20 ng/mL. 1
• Continue ADT for another 7-month cycle. 1
• Stop again if PSA decreases to ≤4 ng/mL. 1
• Repeat this cycle indefinitely unless disease progression occurs. 1

Critical Monitoring Requirements

Patients may need to switch to continuous ADT upon signs of disease progression, including development of castration resistance, symptomatic progression, or radiographic progression despite adequate castration levels. 1, 2

• Maintain castrate serum testosterone levels (<50 ng/dL or <1.7 nmol/L) during on-treatment periods, as this correlates with improved cause-specific survival. 3
• Patients who do not achieve adequate testosterone suppression (<50 ng/dL) can be considered for additional hormonal manipulations, though clinical benefit remains uncertain. 1

Quality of Life Considerations

While intermittent ADT showed better erectile function and mental health at 3 months off treatment in the SWOG trial, these differences became insignificant thereafter. 1 The PR.7 trial (in non-metastatic patients) showed modest improvements in physical function, fatigue, urinary problems, hot flashes, libido, and erectile dysfunction with intermittent therapy. 1

Common Pitfalls to Avoid

• Do not extrapolate results from biochemical recurrence trials (like PR.7) to metastatic disease—the evidence base is different and less favorable for intermittent therapy in metastatic patients. 1, 5
• Do not use intermittent ADT in patients with minimal metastatic disease burden, as post-hoc analysis suggests worse outcomes in this subgroup (HR 1.19). 1
• Do not assume the PSA threshold of 20 ng/mL for restarting therapy is evidence-based—this was chosen for trial design and may not be optimal. 1
• Avoid using intermittent ADT without thorough patient counseling about the inconclusive survival data and need for intensive monitoring. 6, 5

Alternative Standard Approach

Continuous ADT is recommended over intermittent ADT for metastatic hormone-naïve prostate cancer and should be maintained throughout the disease course, with castrate testosterone levels maintained even when disease progresses to castration-resistant prostate cancer. 2, 3, 4