Background
Phase III, double-blind, placebo-controlled RCT. 1401 patients with nmCRPC (castration-resistant, M0 by conventional CT and bone scan), PSA doubling time ≤10 months, PSA ≥2 ng/mL, on ongoing ADT with castrate testosterone ≤50 ng/dL.
Interventions and follow up
Arm A: Enzalutamide 160mg/day orally + ongoing ADT
Arm B: Placebo + ongoing ADT
Primary endpoint: Metastasis-free survival (MFS)
mFollow up: 18.5 mo (MFS primary); 48.0 mo (OS update)
Arm B: Placebo + ongoing ADT
Primary endpoint: Metastasis-free survival (MFS)
mFollow up: 18.5 mo (MFS primary); 48.0 mo (OS update)
Results
MFS: 36.6 vs 14.7 mo, HR 0.29, P<.001
OS: 67.0 vs 56.3 mo, HR 0.73, P=.001
Time to PSA progression: 37.2 vs 3.9 mo, HR 0.07
Time to first metastasis: 36.6 vs 14.7 mo
OS: 67.0 vs 56.3 mo, HR 0.73, P=.001
Time to PSA progression: 37.2 vs 3.9 mo, HR 0.07
Time to first metastasis: 36.6 vs 14.7 mo
Adverse events
Overall grade ≥3 AEs: 31% vs 23%
Constitutional: Fatigue (any grade) 33% vs 14%
Cardiovascular: Major adverse cardiovascular events 5% vs 3%; hypertension grade ≥3 5% vs 3%
Neurologic / musculoskeletal: Falls 11% vs 4%; cognitive disorder 5% vs 2%; seizure 0.1% vs 0%
Treatment discontinuation due to AEs: 9% vs 8%
Constitutional: Fatigue (any grade) 33% vs 14%
Cardiovascular: Major adverse cardiovascular events 5% vs 3%; hypertension grade ≥3 5% vs 3%
Neurologic / musculoskeletal: Falls 11% vs 4%; cognitive disorder 5% vs 2%; seizure 0.1% vs 0%
Treatment discontinuation due to AEs: 9% vs 8%
Conclusions
Enzalutamide significantly prolonged MFS and OS versus placebo in nmCRPC with rapid PSA kinetics, with an HR of 0.29 for MFS representing one of the largest treatment effects in prostate cancer. These results established enzalutamide as a standard of care in nmCRPC.
Key Limitations
Key Limitations: M0 status defined by conventional imaging without PSMA PET — many enrolled patients likely had micrometastatic disease. Open-label crossover to enzalutamide at metastasis development confounds OS interpretation. The modest absolute OS benefit (~11 months) should be weighed against long-term ARPI toxicity including falls, fractures, and cardiovascular risk. PSA DT ≤10 months is a broader inclusion criterion than the ≤6 months used in some other nmCRPC trials.
Clinical Context
PROSPER, alongside SPARTAN (apalutamide) and ARAMIS (darolutamide), defined the modern nmCRPC ARPI treatment paradigm. All three received FDA approval for nmCRPC. Darolutamide has the most favorable CNS and cognitive safety profile due to minimal blood-brain barrier penetration, and is preferred for seizure-prone or polypharmacy patients. PSMA PET has fundamentally altered the nmCRPC landscape — many patients historically enrolled in these trials would now be classified as oligometastatic or mHSPC.
References