Timing of Androgen Deprivation Therapy for Prostate Cancer Patients after Radiation: Planned Combined Analysis of Two Randomized Phase 3 Trials

Abstract

The TOAD (TROG 03.06; NCT00110162) phase 3 randomized trial showed that immediate androgen deprivation therapy (IADT) improved overall survival (OS) and time to clinical progression compared with delayed ADT (DADT) in progressive or relapsed prostate cancer patients after radical radiation therapy (RT) or prostatectomy + RT. ELAAT (NCT00439751) was a similarly designed trial but failed to reach its accrual goal. The two investigative teams planned a combined analysis before ELAAT was activated. This combined analysis seeks to determine if IADT improves a number of clinical outcomes including overall survival. The PSA failures from TOAD and 78/79 patients accrued to ELAAT were combined (1 patient was excluded due to castrate resistant prostate cancer (CRPC)). Participants for both trials were randomized 1:1 to IADT or DADT. The primary endpoint was all-cause mortality by intention-to-treat. Secondary endpoints were cancer-specific mortality (CSM), local progression, distant progression, CRPC, and prostate cancer complications (PCC). A total of 261 patients from TOAD and 78 patients from ELAAT were followed a median of 5.0y. TOAD patients were younger (mean age 70.5 vs 73.8y) and more had a relapse-free interval <2y from RT (30% vs 10%). In the DADT arms, 63% received ADT a median of 1.58y for TOAD; 38% received ADT a median 1.65y for ELAAT. For patients receiving ADT, the mean pre-ADT PSAs were 3.52 and 30.2 ng/ml in the IADT and DADT arms of TOAD and 3.98 and 18.1 ng/ml in ELAAT. There were 60 deaths, 40 and 20 respectively. Overall, for IADT and DADT arms the proportions of deaths in each trial were 15%, 11%, 19% and 26%, 27% and 24%. All-cause mortality (HR 0.75, 95% CI 0.40, 1.41; p = 0.37) and CSM (HR 0.57, 95% CI 0.22, 1.49) were not statistically different between IADT and DADT. Time to local progression (survival time ratio 1.97, 95% CI 1.28, 3.04; p=0.002) and distant progression (survival time ratio 1.28, 95% CI 1.04, 1.58; p=0.02) was higher while PCC (3.7 v 7.5%, p=0.06) was lower with IADT. CRPC outcomes will be presented at conference. No difference in OS was detected between IADT and DADT in the combined analysis. A possible explanation is that ELAAT accrued older patients with lower risk of CSM and had a smaller difference in PSA between the IADT and DADT arms. Not all relapsed men need IADT; many will die without ever needing ADT and never have a complication or develop CRPC. Further work is needed to identify patients who will benefit from IADT and those suitable for DADT.