Re: Testosterone Breakthrough Rates during Androgen Deprivation Therapy for Castration Sensitive Prostate Cancer

Purpose: Androgen deprivation therapy is an established therapy for castration sensitive prostate cancer and recent studies have observed that patients whose testosterone levels are suppressed below 0.7 nmol/l have improved outcomes. Testosterone breakthrough, or a rise in testosterone above a target threshold after the first month of androgen deprivation therapy, is generally associated with treatment deficiency. The purpose of this review is to summarize breakthrough rate data and explore the relationship to clinical outcomes in patients with castration sensitive prostate cancer receiving androgen deprivation therapy. Materials and Methods: Our systematic search identified 45 studies with a total of 52 cohorts representing 6,047 total patients reporting testosterone breakthrough rates or derivative measures above the thresholds of 1.7 nmol/l (51 cohorts, 6,015 patients) or 0.7 nmol/l (15 cohorts, 2,495 patients). Results: Significantly higher weighted mean breakthrough rates were seen for the 0.7 nmol/l threshold compared to 1.7 nmol/l (41.3% vs 6.9%, p < 0.0001). A significant association between breakthrough rates and worse clinical outcomes overall was not found, although when larger trials (sample size greater than 100) and higher event rates (greater than 50%) were considered for the lowest threshold, significant associations between breakthrough rates and clinical outcomes were observed. Clinical factors such as administration and monitoring frequency, type of testosterone assay and type of androgen deprivation therapy did not significantly affect breakthrough rates, although nonvalidated assays were associated with a large degree of variability. Conclusions: Results from our analysis indicate that testosterone breakthroughs likely result in worse clinical outcomes and should be avoided. Moreover, there is a need to standardize assessment of testosterone levels both clinically and in the research context to better inform treatment decisions and improve the reliability and comparability of results across studies.