FORMULA-509: A Multicenter Randomized Trial of Postprostatectomy Salvage Radiotherapy and 6 months of a GNRH Agonist with Either Bicalutamide or Abiraterone Acetate plus Prednisone and Apalutamide

BACKGROUND AND OBJECTIVE: For patients with detectable prostate-specific antigen (PSA) after radical prostatectomy, 6 mo of a GNRH agonist with salvage radiotherapy (sRT) is a standard treatment option. METHODS: FORMULA-509 (NCT03141671) enrolled 345 patients with PSA ≥0.1 ng/ml and high-risk features from November 24, 2017 to March 25, 2020. Patients received sRT plus 6 mo of a GNRH agonist and randomization to bicalutamide (50 mg) or abiraterone acetate + prednisone (AAP; 1000 mg/5 mg) + apalutamide (240 mg) QD. The primary endpoint was PSA progression-free survival (PFS). A secondary endpoint was metastasis-free survival (MFS) on conventional imaging. Stratification was by PSA (>0.5 vs ≤0.5 ng/ml) and pN status (pN0 vs pN1). KEY FINDINGS AND LIMITATIONS: Median follow-up was 34 mo. AAP + apalutamide did not reach the prespecified significance level for PFS benefit in comparison to bicalutamide (hazard ratio [HR] 0.71. 90% confidence interval [CI] 0.49-1.03; stratified one-sided log-rank p = 0.063), with 3-yr PFS rates of 68.5% with bicalutamide versus 74.9% with AAP + apalutamide. The HR for MFS was 0.57 (90% CI 0.33-1.01; stratified one-sided p = 0.050) and the 3-yr MFS rates were 87.2% with bicalutamide versus 90.6% with AAP + apalutamide. A preplanned analysis by stratification factors revealed that for patients with PSA >0.5 ng/ml, AAP + apalutamide was associated with superior PFS (HR 0.50, 95% CI 0.27-0.95; 2-sided p = 0.030; 3-yr PFS 46.8% with bicalutamide vs 67.2% with AAP + apalutamide) and MFS (HR 0.32, 95% CI 0.13-0.84; 2-sided p = 0.014; 3-yr MFS 66.1% with bicalutamide vs 84.3% with AAP + apalutamide). Adverse events were consistent with the known safety profiles of the study agents, with more frequent rash and hypertension in the AAP + apalutamide arm. CONCLUSIONS AND CLINICAL IMPLICATIONS: This study did not reveal a benefit for the overall population, but addition of AAP + apalutamide (vs bicalutamide) to sRT and ADT improved PFS and MFS in the prespecified subgroup with PSA >0.5 ng/ml.