CHICAGO, IL USA (UroToday.com) - Dr. Gillian Duchesne, a radiation oncologist from the Peter MacCallum Cancer Center in Melbourne, Australia, presented the initial results of the TOAD study, a phase III randomized clinical trial assessing the timing of androgen deprivation therapy (ADT) among asymptomatic men with biochemical recurrence of prostate cancer. The investigators sought to determine whether early initiation of ADT among men with biochemical recurrence who lack further curative treatment options is associated with better outcomes than later treatment with ADT. They hypothesized that immediate treatment with ADT at the time of diagnosis with recurrence would improve overall survival and have an acceptable toxicity and quality of life profile as compared to delayed initiation of ADT.
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There were two patient groups in the study. The first (study 1) included men who had undergone one or more treatments with curative intent with subsequent PSA relapse, and the second (study 2) included men with asymptomatic newly diagnosed prostate cancer who were not being considered for treatment with curative intent. Men in both study groups were randomized to treatment with immediate ADT vs delayed ADT, and the investigators combined the data from the two groups to analyze the study. The investigators stratified for prior treatment (surgery and/or radiation), relapse-free interval (< 2 years vs ≥ 2 years), type of ADT planned (continuous vs intermittent), treatment center, and PSA doubling time (< 10 months or ≥ 10 months). Delayed treatment was defined as not initiating treatment with ADT for at least 2 years, if clinically appropriate, unless PSA doubling time was < 12 months and PSA > 10 ug/L (study 1), or if patients with metastatic disease had a PSA > 60 ug/L, or PSA doubling time was < 6 months (study 2). The study’s primary endpoint was overall survival (OS), and secondary outcomes included cancer-specific and disease-free survival, quality of life, morbidity of treatment, and complications from therapy.
The patients were very similar between the early and delayed treatment arms in both studies, and the investigators pooled the results from both to analyze the data. Both 5 and 6 year OS was better with immediate treatment with ADT as compared with delayed treatment (5 year OS was 85.6% vs 76.4% for immediate vs delayed ADT; and 6 year OS was 81.0% vs 65.4% for immediate vs delayed ADT). The unadjusted hazard ratio (HR) for survival between groups was 0.55 (95% CI 0.30 – 1.00; p=0.05) favoring immediate treatment with ADT. The adjusted HR demonstrated a trend toward improvement with immediate treatment at 0.54 (95% CI 0.27 – 1.06; p=0.074). Median survival was not reached on either arm of the study after 8 years of follow-up. Prostate cancer deaths were not significantly reduced, though there was a slight trend toward reduction associated with early treatment (HR 0.50, 95% CI 0.18 – 1.60; p=0.26). Other causes of death also appeared to be reduced with treatment. There were few events driving both of these secondary endpoint analyses, and further information may alter this with continued follow-up. In further, unplanned, secondary analyses, intermittent ADT appeared to be associated with a trend toward improved OS as compared to continuous ADT (HR 0.46, 95% CI 0.20 – 1.04; p=0.06 in the immediate treatment arm, though this was not the case in the delayed treatment arm (HR 1.01, 95% CI 0.48 – 2.10; p = 0.98 for intermittent compared with continuous ADT). Times to first local progression and to first metastatic disease were also significantly improved with immediate ADT as compared with delayed ADT.
The investigators also assessed morbidity and compared health-related quality of life between the immediate and delayed ADT treatment groups. Immediate ADT was associated with longer time to first prostate cancer complication when compared to the delayed treatment group (HR 0.78, 95% CI 0.54 – 1.11; p = 0.16), and 34% vs 41% of men with delayed and immediate ADT, respectively, experienced a complication of prostate cancer. In terms of ADT-related symptoms, 77.9% of men treated with immediate ADT reported ADT-related symptoms during the course of the study, vs 47.3% of men in the delayed treatment arm. Importantly, 34.7% of men in the delayed treatment arm received ADT prior to the end of the 2-year planned delay period.
This study suggests that the use of early ADT for men with biochemical recurrence, and those unfit for curative treatment, may achieve a 10% improvement in OS at 5 years with treatment with immediate ADT. This benefit may be delivered with a tolerable side effect profile, though men treated with immediate ADT have a significantly higher risk of ADT-associated side effects than men treated with delayed ADT. Ultimately the study provides evidence of benefit to early treatment with ADT in this population, and does so in a randomized, controlled trial. The difficulty that the team had with accrual makes it unlikely that this type of study will be repeated. As such, we eagerly await future data to determine the secondary endpoint outcomes assessed by this trial.
Presented by Gillian M. Duchesne at the American Society of Clinical Oncology (ASCO) Annual Meeting - Illumination & Innovation: Transforming Data into Learning - May 29 - June 2, 2015 - Chicago, Illinois USA
Peter MacCallum Cancer Centre, Melbourne, Australia