**1. Introduction**

Androgen-deprivation therapy (ADT) is the standard initial systemic therapy for advanced prostate cancer (PCa). Generally, ADT is performed with surgical castration or pharmacologic castration (luteinizing hormone-releasing hormone agonist or antagonist) accompanied with/without an antiandrogen (combined androgen blockade: CAB). Even PCa patients with metastatic disease initially respond well to ADT, but most eventually progress to castration-resistant prostate cancer (CRPC), which has a high mortality rate. Thus, there is an urgen<sup>t</sup> need for predictors of which patients are more likely to develop CRPC. Several prognostic factors identified in clinical and laboratory studies could be used to predict survival including performance status, T stage, and extent of bone metastases, as well as serum alkaline phosphatase, hemoglobin, and testosterone levels [1,2]. The J-CAPRA score is a novel, validated score encompassing initial prostate-specific antigen (PSA) levels, Gleason score, and clinical stage that can be used to predict outcomes among patients undergoing primary ADT who represent the full spectrum of risk and stage, including advanced disease [3].

PSA is currently the most useful biomarker for detection of PCa. The ability to measure serum PSA levels affected all aspects of PCa managemen<sup>t</sup> over the past two decades. Serum PSA levels are generally proportional to tumor volume and clinical stage of the disease. Thus, despite recognized limitations, measurement of PSA is essential for screening and monitoring of treatment response, prognosis, and progression in patients with PCa [4]. We demonstrated that time to PSA nadir (TTN) after primary ADT is an important early predictor for overall survival and progression-free survival

for advanced PCa patients [5,6]. Moreover, we gathered evidence from in vivo experiments to support the role of fibroblasts in the PCa tumor microenvironment in prolonging the period of serum PSA decline after ADT and enhancing the efficacy of ADT [7]. In this review, we briefly summarize the importance of TTN after primary ADT for hormone-naïve advanced PCa patients with a focus on results from both in vitro and in vivo experiments.
