Enzalutamide in First-Line Castrate-Sensitive Prostate Cancer: Progression-Free Survival and Response Data
For metastatic castration-sensitive prostate cancer, enzalutamide demonstrates exceptional radiographic progression-free survival with a median not reached in the ARCHES trial versus 19.0 months for placebo (61% risk reduction, HR 0.39), representing the most robust first-line PFS data available. 1
Radiographic Progression-Free Survival
The ARCHES trial provides the definitive PFS data for enzalutamide in first-line metastatic castration-sensitive disease:
- Primary endpoint: Radiographic PFS was not reached in the enzalutamide plus ADT arm versus 19.0 months with placebo plus ADT after median follow-up of 14.4 months (HR 0.39; 95% CI 0.30-0.50; P < 0.001) 1
- This represents a 61% reduction in the risk of radiographic progression or death 1
- The trial enrolled 1,150 patients with metastatic castration-sensitive prostate cancer, stratified by disease volume and prior docetaxel use 1
Overall Survival Benefit
While PFS is impressive, the mortality benefit solidifies enzalutamide's role:
- Final OS analysis: 34% reduction in risk of death with enzalutamide versus placebo (HR 0.66; 95% CI 0.53-0.81; P < 0.001) 1
- Median OS was not reached in either arm at final analysis, though approximately 32% of placebo patients crossed over to enzalutamide after unblinding, potentially underestimating the true survival benefit 1
Supporting Evidence from ENZAMET Trial
The ENZAMET trial provides complementary data comparing enzalutamide to first-generation antiandrogens:
- PSA-based PFS and clinical PFS: Both significantly improved as secondary endpoints (specific median values not provided in guideline excerpts) 1
- Overall survival: HR 0.67 (95% CI 0.52-0.86; P = 0.002) at first interim analysis with 34-month median follow-up 1
- Extended follow-up (68 months): 5-year OS rate favored enzalutamide with HR 0.70 (95% CI 0.58-0.84; P < 0.0001); median OS not reached 1
Response Rates and Secondary Endpoints
Beyond PFS, enzalutamide demonstrates robust biochemical and clinical responses:
- PSA decline ≥50%: 78% with enzalutamide versus 3% with placebo in chemotherapy-naïve metastatic CRPC (PREVAIL trial data, though this was castration-resistant not castration-sensitive) 2
- Time to PSA progression: Significantly delayed (HR 0.17 in PREVAIL) 2
- Quality of life: Health-related QOL maintained during treatment in castration-sensitive setting 1
Safety Profile in First-Line Setting
The adverse event profile in castration-sensitive disease mirrors that seen in castration-resistant trials:
- Most common adverse events: Fatigue, seizures, and hypertension 1
- Fatigue: 33-34% versus 14% with placebo 1
- Hypertension: 12% versus 5% with placebo 1
- Seizure risk: 0.6-0.9% (7 patients [1%] in ENZAMET) 3
- Mental impairment disorders: 5% versus 2% with placebo 1
- Major adverse cardiovascular events: 5% versus 3% with placebo 1
FDA Approval and Guideline Recommendations
Enzalutamide received FDA approval for metastatic castration-sensitive prostate cancer in December 2019 and is designated as a Category 1 (highest level of evidence and consensus) treatment option by NCCN. 1
Practical Considerations
- Dosing: 160 mg orally once daily with continued ADT (LHRH analog or surgical castration) 1, 4
- Food restrictions: None required 1
- Concurrent prednisone: Permitted but not required 1
- Time to steady-state: Achieved by Day 28 with approximately 8.3-fold accumulation 4
Important Clinical Caveats
The ARCHES trial's crossover design (32% of placebo patients received enzalutamide after unblinding) means the OS benefit may be underestimated 1. Additionally, while triplet therapy (ADT plus docetaxel plus novel hormone therapy like enzalutamide) shows improved outcomes in high-volume disease, the question specifically addresses enzalutamide as first-line therapy, where doublet therapy (enzalutamide plus ADT) remains the standard approach for patients not receiving concurrent chemotherapy 1.