What are the risk factors for early progression on enzalutamide (anti-androgen therapy)?

Risk Factors for Early Progression on Enzalutamide

The most significant risk factors for early progression on enzalutamide include high disease volume, prior docetaxel chemotherapy treatment, and rapid PSA doubling time (≤10 months). These factors should be carefully evaluated when considering enzalutamide therapy for patients with prostate cancer.

Disease Characteristics Associated with Early Progression

High Disease Volume

• Patients with high-volume disease (HVD) as defined in clinical trials may experience earlier progression on enzalutamide compared to those with low-volume disease (LVD)
• In the ENZAMET trial, approximately 50% of men had HVD at baseline, which influenced treatment outcomes 1

Prior Treatments

• Prior docetaxel chemotherapy may impact response to enzalutamide
• In the ENZAMET trial, approximately 16% of patients had received prior docetaxel chemotherapy, which may affect long-term outcomes 1
• The effect of ADT plus enzalutamide on radiographic progression-free survival was consistently favorable across most subgroups, but the benefit was less clear in those with previous docetaxel use 1

PSA Kinetics

• Rapid PSA doubling time (PSADT ≤10 months) is associated with higher risk of progression
• In the PROSPER trial, patients with PSADT ≤10 months were at higher risk for developing metastatic disease 1
• Even small increases in PSA while on enzalutamide may indicate early disease progression and warrant closer monitoring 2

Monitoring for Early Progression

PSA Monitoring Considerations

• The median PSA increase from nadir at the time of radiographic progression was only 1.4 ng/mL in enzalutamide-treated men compared to 25.6 ng/mL for placebo 2
• This suggests that traditional PSA progression definitions may not adequately predict radiographic progression in enzalutamide-treated patients
• Any rise in PSA, even below the traditional Prostate Cancer Working Group 2 (PCWG2) threshold, may require closer monitoring 2

Radiographic Assessment

• Regular imaging is essential as radiographic progression often occurs without meeting traditional PSA progression criteria
• In enzalutamide-treated patients, the risk of metastasis or death was increased significantly in those with PSA progression versus those without (HR 3.99; 95% CI, 2.95-5.41; p<0.0001) 2

Clinical Implications

Treatment Selection

• For patients with high-risk features for early progression, consider alternative or additional therapies
• The NCCN guidelines recommend enzalutamide as a category 1, preferred treatment option for patients without prior novel hormone therapy in the mCRPC setting 1
• For patients with mCRPC and prior novel hormone therapy, enzalutamide is included in the "other recommended regimens" group of options 1

Adverse Events to Monitor

• Common adverse events that may lead to discontinuation include fatigue (33% vs 14%), hypertension (12% vs 5%), and major adverse cardiovascular events (5% vs 3%) 1
• Mental impairment disorders (5% vs 2%) and seizures (0.6%) are less common but important to monitor 1, 3

Practical Approach to Monitoring

1. Establish baseline PSA and radiographic disease assessment before starting enzalutamide
2. Monitor PSA more frequently in patients with high-risk features (every 1-2 months)
3. Consider more frequent imaging in patients with any PSA rise, even if below traditional progression thresholds
4. Be vigilant for clinical symptoms that may indicate progression despite stable PSA
5. Have a lower threshold for radiographic assessment in patients with high-risk features

By understanding these risk factors and implementing appropriate monitoring strategies, clinicians can optimize treatment outcomes for patients receiving enzalutamide therapy.