Background
Phase III, double-blind, placebo-controlled RCT. 1207 patients with nmCRPC (castration-resistant, M0 by conventional CT and bone scan), PSA doubling time ≤10 months, PSA ≥2 ng/mL, on ongoing ADT.
Interventions and follow up
Arm A: Apalutamide 240mg/day orally + ongoing ADT
Arm B: Placebo + ongoing ADT
Primary endpoint: Metastasis-free survival (MFS)
mFollow up: 20.3 mo (MFS primary); 52 mo (OS update)
Arm B: Placebo + ongoing ADT
Primary endpoint: Metastasis-free survival (MFS)
mFollow up: 20.3 mo (MFS primary); 52 mo (OS update)
Results
MFS: 40.5 vs 16.2 mo, HR 0.28, P<.001
OS: 73.9 vs 59.9 mo, HR 0.78, P=.016
PFS: 40.5 vs 14.7 mo, HR 0.29
Time to symptomatic progression: HR 0.45
OS: 73.9 vs 59.9 mo, HR 0.78, P=.016
PFS: 40.5 vs 14.7 mo, HR 0.29
Time to symptomatic progression: HR 0.45
Adverse events
Overall grade ≥3 AEs: 45.1% vs 34.2%
Dermatologic / endocrine: Rash (any grade) 23.8% vs 5.5% (grade ≥3 5.2%); hypothyroidism 8.1% vs 2.0%
Constitutional: Fatigue 30.4% vs 21.1%
Musculoskeletal / neurologic: Falls 15.6% vs 9.0%; fracture 11.7% vs 6.5%; seizure 0.2% vs 0%
Treatment discontinuation due to AEs: 14.6% vs 8.2%
Dermatologic / endocrine: Rash (any grade) 23.8% vs 5.5% (grade ≥3 5.2%); hypothyroidism 8.1% vs 2.0%
Constitutional: Fatigue 30.4% vs 21.1%
Musculoskeletal / neurologic: Falls 15.6% vs 9.0%; fracture 11.7% vs 6.5%; seizure 0.2% vs 0%
Treatment discontinuation due to AEs: 14.6% vs 8.2%
Conclusions
Apalutamide significantly prolonged MFS and OS versus placebo in nmCRPC, achieving one of the largest MFS effects reported in prostate cancer (HR 0.28). The trial is distinguished by a notable skin rash rate and hypothyroidism incidence compared to other ARPIs in this setting.
Key Limitations
Key Limitations: M0 status was defined by conventional CT and bone scan without PSMA PET, likely including patients with micrometastatic disease. Open-label crossover at metastasis detection confounds OS interpretation. Apalutamide's rash (~24%) and hypothyroidism (~8%) rates exceed those of enzalutamide and darolutamide — thyroid monitoring is required. Drug interactions via CYP2C8/3A4 induction may affect co-administered medications. The mechanism of hypothyroidism is incompletely understood.
Clinical Context
Apalutamide (SPARTAN) is one of three FDA-approved ARPIs in nmCRPC alongside enzalutamide (PROSPER) and darolutamide (ARAMIS). Apalutamide is also approved in mHSPC based on TITAN. Among the three nmCRPC agents, darolutamide is often preferred for patients at CNS risk or on polypharmacy; apalutamide is associated with rash and hypothyroidism requiring monitoring. PSMA PET now routinely reclassifies patients previously deemed nmCRPC.
References