Background
Phase III double-blind RCT of 1,199 men with metastatic castration-resistant prostate cancer (mCRPC) after one or two chemotherapy regimens (docetaxel-based). Randomized 2:1 to enzalutamide vs placebo, both continuing androgen-deprivation therapy.
Interventions and follow up
Arm A: Enzalutamide 160 mg PO daily
Arm B: Placebo
Primary endpoint: Overall survival
Median follow up: 14.4 mo
Arm B: Placebo
Primary endpoint: Overall survival
Median follow up: 14.4 mo
Results
OS: 18.4 mo vs 13.6 mo (A vs B); HR 0.63, 95% CI 0.53-0.75; P<.001
PSA response rate: 54% vs 2%; P<.001
Soft-tissue response rate: 29% vs 4%; P<.001
Quality-of-life response: 43% vs 18%; P<.001
Time to PSA progression: 8.3 mo vs 3.0 mo; P<.001
Radiographic PFS: 8.3 mo vs 2.9 mo; P<.001
PSA response rate: 54% vs 2%; P<.001
Soft-tissue response rate: 29% vs 4%; P<.001
Quality-of-life response: 43% vs 18%; P<.001
Time to PSA progression: 8.3 mo vs 3.0 mo; P<.001
Radiographic PFS: 8.3 mo vs 2.9 mo; P<.001
Adverse events
Grade 3-4 events: 45.3% vs 53.1% (A vs B)
Constitutional: Fatigue 34% vs 29%; hot flash 20% vs 10%
Gastrointestinal: Diarrhea 21% vs 18%
Musculoskeletal: Musculoskeletal pain 14% vs 10%
Neurologic: Seizure 0.6% vs 0%
Constitutional: Fatigue 34% vs 29%; hot flash 20% vs 10%
Gastrointestinal: Diarrhea 21% vs 18%
Musculoskeletal: Musculoskeletal pain 14% vs 10%
Neurologic: Seizure 0.6% vs 0%
Conclusions
Enzalutamide significantly prolonged overall survival and improved PSA response, quality of life, time to PSA progression, soft-tissue response, and radiographic PFS versus placebo in men with mCRPC progressing after docetaxel.
Key Limitations
Post-docetaxel population only; modern combination first-line regimens not reflected. No active comparator. Rare seizure signal limited generalizability to patients at seizure risk.
Clinical Context
AFFIRM led to FDA approval of enzalutamide (2012) for post-docetaxel mCRPC; the subsequent PREVAIL trial extended approval to the pre-chemotherapy mCRPC setting. Enzalutamide is an ESMO/ASCO-endorsed androgen-receptor pathway inhibitor option across the castration-resistant disease continuum.
References
Scher HI et al, NEJM, 2012, PMID 22894553
Beer TM et al (PREVAIL), NEJM, 2014, PMID 24881730
Beer TM et al (PREVAIL), NEJM, 2014, PMID 24881730