Loss of SLCO1B3 drives taxane resistance in prostate cancer.

BACKGROUND: Both taxanes, docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. METHODS: Two docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-docetaxel resistance and gene expression profiles were compared. [(14)C]-docetaxel and [(14)C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. RESULTS: Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to docetaxel and cabazitaxel. CONCLUSIONS: The SLCO1B3 determines intracellular concentrations of docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.

Association of Survival Benefit With Docetaxel in Prostate Cancer and Total Number of Cycles Administered: A Post Hoc Analysis of the Mainsail Study.

IMPORTANCE: The optimal total number of docetaxel cycles in patients with metastatic castration resistant prostate cancer (mCPRC) has not been investigated yet. It is unknown whether it is beneficial for patients to continue treatment upon 6 cycles. OBJECTIVE: To investigate whether the number of docetaxel cycles administered to patients deriving clinical benefit was an independent prognostic factor for overall survival (OS) in a post hoc analysis of the Mainsail trial. DESIGN, SETTING, AND PARTICIPANTS: The Mainsail trial was a multinational randomized phase 3 study of 1059 patients with mCRPC receiving docetaxel, prednisone, and lenalidomide (DPL) or docetaxel, prednisone, and a placebo (DP). Study patients were treated until progressive disease or unacceptable adverse effects occurred. Median OS was found to be inferior in the DPL arm compared with the DP arm. As a result of increased toxic effects with the DPL combination, patients on DPL received fewer docetaxel cycles (median, 6) vs 8 cycles in the control group. As the dose intensity was comparable in both treatment arms, we investigated whether the number of docetaxel cycles administered to patients deriving clinical benefit on Mainsail was an independent prognostic factor for OS. We conducted primary univariate and multivariate analyses for the intention-to-treat population. Additional sensitivity analyses were done, excluding patients who stopped treatment for reasons of disease progression and those who received 4 or fewer cycles of docetaxel for other reasons, minimizing the effect of confounding factors. MAIN OUTCOMES AND MEASURES: Total number of docetaxel cycles delivered as an independent factor for OS. RESULTS: Overall, all 1059 patients from the Mainsail trial were included (mean [SD] age, 68.7 [7.89] years). Treatment with 8 or more cycles of docetaxel was associated with superior OS (hazard ratio [HR], 1.909; 95% CI, 1.660-2.194; P < .001), irrespective of lenalidomide treatment (HR, 1.060; 95% CI, 0.924-1.215; P = .41). Likewise, in the sensitivity analysis, patients who received a greater number of docetaxel cycles had superior OS; patients who received more than 10 cycles had a median OS of 33.0 months compared with 26.9 months in patients treated with 8 to 10 cycles; and patients who received 5 to 7 cycles had a median OS of 22.8 months (P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that continuation of docetaxel chemotherapy contributes to the survival benefit. Prospective validation is warranted.

Inter-patient variability in docetaxel pharmacokinetics: A review.

Docetaxel is a frequently used chemotherapeutic agent in the treatment of solid cancers. Because of the large inter-individual variability (IIV) in the pharmacokinetics (PK) of docetaxel, it is challenging to determine the optimal dose in individual patients in order to achieve optimal efficacy and acceptable toxicity. Despite the established correlation between systemic docetaxel exposure and efficacy, the precise factors influencing docetaxel PK are not yet completely understood. This review article highlights currently known factors that influence docetaxel PK, and focusses on those that are clinically relevant. For example, liver impairment should be taken into account when calculating docetaxel dosages as this may decrease docetaxel clearance. In addition, drug-drug interactions may be of distinct clinical importance when using docetaxel. Particularly, drugs strongly inhibiting CYP3A4 such as ketoconazole should not be concurrently administered without dose modification, as they may decrease the clearance of docetaxel. Gender, castration status, and menopausal status might be of importance as potential factors influencing docetaxel PK. The role of pharmacogenetics in predicting docetaxel PK is still limited, since no polymorphisms of clinical importance have yet been established.

Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer.

UNLABELLED: Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC. PATIENT SUMMARY: We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.

Initial biopsy Gleason score as a predictive marker for survival benefit in patients with castration-resistant prostate cancer treated with docetaxel: data from the TAX327 study.

BACKGROUND: Since 2004, docetaxel has been the standard first-line systemic therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). With abiraterone recently becoming available in the predocetaxel setting, it is warranted to identify subgroups of patients who may obtain the greatest benefit from docetaxel and particularly qualify for receiving docetaxel as first-line treatment for mCRPC. OBJECTIVE: We aimed to identify factors that could characterize subgroups of patients who obtain the greatest benefit from the use of docetaxel. DESIGN, SETTING, AND PARTICIPANTS: TAX327 was multinational, randomized, phase 3 study that was conducted from 2000 to 2002 in 1006 men with mCRPC. INTERVENTION: Patients were randomized to receive docetaxel every 3 wk (D3), weekly docetaxel (D1), or mitoxantrone every 3 wk (M3), each with prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We investigated whether patients with poorly differentiated tumors (Gleason score ≥7) at diagnosis had greater benefit from D3 compared with M3 than patients with better differentiated tumors (Gleason score ≤6). Using a Cox model, we compared overall survival (OS) between the treatment groups within each subgroup of Gleason score. RESULTS AND LIMITATIONS: The TAX 327 data showed that the OS benefit of D3 versus M3 was greater in patients with high-grade tumors (median OS: 18.9 vs 14.5 mo; p=0.009) than in patients with low-grade tumors (median OS: 21.6 vs 20.7 mo; p=0.674). Limitations of a retrospective analysis apply. CONCLUSIONS: The survival benefit obtained with docetaxel is most pronounced in patients with high-Gleason-score tumors (Gleason ≥7). In a time of shifting paradigms in mCRPC, with abiraterone becoming available prior to docetaxel chemotherapy, Gleason score may help in selecting patients who obtain the greatest benefit from docetaxel as first-line treatment for mCRPC. Prospective validation of these findings is warranted.

Nuclear Eg5 (kinesin spindle protein) expression predicts docetaxel response and prostate cancer aggressiveness.

Novel biomarkers predicting prostate cancer (PCa) aggressiveness and docetaxel therapy response of PCa patients are needed. In this study the correlation between nuclear Eg5-expression, PCa docetaxel response and PCa aggressiveness was assessed. Immunohistochemical staining for nuclear Eg5 was performed on 117 archival specimens from 110 PCa patients treated with docetaxel between 2004 and 2012. Samples were histologically categorized as positive/negative. Median follow-up time from diagnosis was 11.6 years. Nuclear Eg5-expression was significantly related to docetaxel response (p=0.036) in tissues acquired within three years before docetaxel initiation. Nuclear Eg5-expression was not related to Gleason-score (p=0.994). Survival of patients after docetaxel initiation did not differ based on nuclear Eg5-expression (p=0.540). Analyzing samples taken before hormonal therapy, overall survival and time to docetaxel use were significantly decreased in patients with nuclear Eg5-expressing tumors (p<0.01). Eg5-positive nuclei were found more frequently in T4-staged tumors (p=0.04), Gleason 8-10 tumors (p=0.08), and in metastasized tumors (p<0.01). Multivariate analyses indicated that nuclear Eg5-expression may be an independent parameter for tumor aggressiveness. Limitations of a retrospective analysis apply. In conclusion, nuclear Eg5-expression may be a predictive biomarker for docetaxel response in metastatic castrate-resistant PCa patients and a prognostic biomarker for hormone-naive PCa patients. Prospective validation studies are needed.