In this study, we demonstrate that TT and FT serum levels are reduced during docetaxel chemotherapy and that FT suppression under the detection limit (100%) resulted in better PFS and OS in mCNPC and mCRPC patients, but not in mCRPC patients with a history of ART. Interestingly, in contrast to TT, only FT was a significant predictor for PFS and OS, demonstrating a major biological role of FT for treatment outcome. mCRPC-ART patients had a significantly lower FT reduction rate due to low FT levels at baseline (8/27 versus 6/7 and 11/20, respectively) and FT reduction was no longer a predictor for better PFS or OS (Table 2). mCRPC-ART patients experienced a lower PSAR and shorter PFS and OS. These results are consistent with several previous studies that showed decreased efficacy of docetaxel in PC patients with a history of ART [11, 12, 21, 22]. Our data suggest that the worst clinical outcome of mCRPC-ART patients towards docetaxel is due to progressing castration resistance.
Multiple lines of evidence suggest that docetaxel and prednisone might directly interfere with testosterone biosynthesis and metabolism in mPC patients and contribute to this FT suppressing effect. Prednisone was demonstrated to lower serum TT, androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels in some metastatic PC patients by suppressing the hypothalamic-pituitary-adrenal axis, but had no antitumor activity in mCRPC [23, 24]. Consistent with this observation, a history of previous prednisone treatment had no effect in multivariate analyses on PFS or OS in our study.
The role of docetaxel in reducing testosterone is less clear, although serum androgens (TT, androstendione and DHEA) decline during docetaxel treatment . Docetaxel metabolism is largely catalyzed by CYP3A4  and docetaxel was shown to induce CYP3A4, which is responsible for the greatest portion of testosterone 6β- and 16β-hydroxylation [26–28]. CYP3A4 induction may lower testosterone levels by inactivation through 6β- and 16β-hydroxylation. The effect of docetaxel on CYP17A1 is unclear [26–28].
Franke et al. reported castration-dependent pharmacokinetics of docetaxel in PC patients. Docetaxel clearance was increased by approximately 100% in castrated men and was associated with a two-fold reduction in area under the curve, although hepatic activity of CYP3A4 was unchanged . Conversely, castration-naïve patients were exposed to higher amounts of the drug, accompanied by more severe hematotoxicity . This study also demonstrated that lower intracellular docetaxel levels caused by lower levels of testosterone resulted in a lower response rate to treatment . Consistent with these results, group 1 patients (mCNPC) had a significantly higher rate of grade 3 and 4 neutropenia compared to group 3 patients (mCRPC-ART) in our study (57.1% vs. 20.6%, p = 0.047; Table 2) and a significantly better clinical outcome (Figs. 2 & 3, Table 2).
Ryan et al. showed that conversion from higher to lower androgen levels (e.g. above/below median) during docetaxel therapy contributed to superior survival as the reduction is the driving mechanism behind the clinical responses . Consistent with these findings, 6/7 (85.7%) mCNPC patients in our study underwent a complete (= 100%) and one patient a nearly complete (99.3%) FT reduction and had a PSA response rate of 100%.
In recent years, several large phase 3 trials in patients with mCNPC (e.g. CHAARTED, STAMPEDE, GETUG-3, LATTITUDE, TITAN, PREVAIL) demonstrated that the addition of docetaxel and ART (abiraterone, apalutamide and enzalutamide) to ADT is associated with significant improvements in PFS and/or OS compared to ADT alone . Our data demonstrate that docetaxel therapy is associated with similarly low testosterone levels (FT + TT) as achieved by Abiraterone + ADT (Fig. 1, Table 1&2).
Our study has some limitations, due to its retrospective design. The population size is small and FT and TT measurements – although excessive in number - were not always assessed on a regular basis (e.g. weekly). Furthermore, progression was mainly due to PSA progression (e.g. PSA progression or radiographic progression, whichever presented first). Despite all of our efforts to address possible lead-time bias (extended time-dependent Cox modelling (T_; ln(T_); T_≥365 days), log(-log(survival probability)) and conditional landmark analyses), there is still the risk that our analyses are subject to lead-time bias, as group 3 patients (mCRPC-ART) had more advanced disease at baseline compared to groups 1 (mCNPC) and 2 (mCRPC). Group 1 was small due to a recent trend towards abiraterone treatment in this setting and patients had a very high-volume disease that required intensive treatment. In addition, scanning intervals were not always uniformly assessed and confirmatory scans were not conducted in general.