Irrefutable evidence for the use of docetaxel in newly diagnosed metastatic prostate cancer: Results from the STAMPEDE and CHAARTED trials

Androgen deprivation therapy (ADT) has been used in the treatment of metastatic prostate cancer since the first description of its hormonal dependence in 1941. In 2004, docetaxel chemotherapy became the mainstay of treatment in metastatic castration-resistant prostate cancer (mCRPC), following robust, albeit modest, survival benefit in two randomized phase 3 trials. The recently published CHAARTED trial was the first to show that combining ADT with docetaxel in men with hormone-naïve (hormone-sensitive) metastatic prostate cancer (mHSPC) yielded a remarkable overall survival benefit of 13.6 months as compared with ADT alone. In the current issue of The Lancet, James et al. report results of the STAMPEDE trial in men with high-risk locally advanced or metastatic prostate cancer initiating long-term hormone therapy. The combination of six cycles of docetaxel with ADT in men commencing long-term ADT demonstrated a similar OS benefit compared with standard of care (SOC) by a median of 10 months. Based on the consistency of the data and the firmness of the benefit provided, docetaxel in addition to ADT should be considered SOC for men with newly diagnosed mHSPC

Abirateron in combinatie met androgeendeprivatietherapie bij patiënten met hormoonnaïef gemetastaseerd prostaatcarcinoom: Is het tijdperk van androgeendeprivatie-monotherapie voorbij?

Data van twee gerandomiseerde studies hebben aangetoond dat abirateron plus prednison, gecombineerd met androgeendeprivatietherapie (ADT) de overleving verbetert van patiënten met primair gemetastaseerd hormoonnaïef prostaatcarcinoom (mHSPC) in vergelijking met ADT alleen (hazardratio 0,62 en 0,63). De belangrijkste bijwerkingen (hypokaliëmie en hypertensie) waren mild (graad 1–2) en goed te behandelen. Voor patiënten met hoogrisico lokaal gevorderd of lymfogeen gemetastaseerd prostaatcarcinoom zonder metastasen op afstand was er een winst in progressievrije overleving, maar zijn de data nog te immatuur om overlevingswinst aan te tonen. Voor patiënteTwo randomized trials have shown that abiraterone plus prednisone and androgen-deprivation therapy (ADT) improved surviv

Prognostic factors in men with metastatic castration-resistant prostate cancer treated with cabazitaxel

Background: Treatment selection for men with metastatic castration-resistant prostate cancer (mCRPC) has become increasingly challenging with the introduction of novel therapies at earlier disease stages. The purpose of this study was to identify prognostic factors for overall survival (OS) and PSA response in patients with mCRPC treated with cabazitaxel. Results: 224 mCRPC patients were included in the current analysis. In multivariable analysis, WHO performance status, baseline hemoglobin, alkaline phosphatase and albumin were all significantly associated with OS. Hemoglobin and alkaline phosphatase were significantly associated with PSA response. Conclusions: This study identified prognostic factors for OS and PSA response of men with mCRPC treated with cabazitaxel. In an increasingly complicated treatment landscape with several treatment options available our findings might serve to estimate the chance of survival of men qualifying for treatment with second-line chemotherapy in daily practice. Furthermore, these data can be used to risk-stratify patients in clinical trials. Methods: We performed a post-hoc analysis of a randomized phase II trial of mCRPC patients treated with cabazitaxel. Cox and logistic regression models were used to investigate the influence of clinical and biochemical variables on OS and PSA response. Nomograms were developed to estimate the chance of PSA response and OS

A bypass mechanism of abiraterone-resistant prostate cancer: Accumulating CYP17A1 substrates activate androgen receptor signaling

Background: Intratumoral steroidogenesis and its potential relevance in castration‐ resistant prostate cancer (CRPC) and in cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1)‐inhibitor treated hormone‐naïve and patients with CRPC are not well established. In this study, we tested if substrates for de novo steroidogenesis accumulating during CYP17A1 inhibition may drive cell growth in relevant preclinical models. Methods: PCa cell lines and their respective CRPC sublines were used to model CRPC in vitro. Precursor steroids pregnenolone (Preg) and progesterone (Prog) served as substrate for de novo steroid synthesis. TAK700 (orteronel), abiraterone, and small interfering RNA (siRNA) against CYP17A1 were used to block CYP17A1 enzyme activity. The antiandrogen RD162 was used to assess androgen receptor (AR) involvement. Cell growth was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. AR‐ target gene expression was quantified by reverse transcription polymerase chain reaction (RT‐PCR). Nuclear import studies using cells with green fluorescent protein (GFP)‐tagged AR were performed to assess the potential of precursor steroids to directly activate AR. Results: Preg and Prog stimulated cell proliferation and AR target gene expression in VCaP, DuCaP, LNCaP, and their respective CRPC sublines. The antiandrogen RD162, but not CYP17A1 inhibition with TAK700, abiraterone or siRNA, was able to block Preg‐ and Prog‐induced proliferation. In contrast to TAK700, abiraterone also affected dihydrotestosterone‐induced cell growth, indicating direct AR binding. Furthermore, Prog‐induced AR translocation was not affected by treatment with TAK700 or abiraterone, while it was effectively blocked by the AR antagonist enzalutamide, further demonstrating the direct AR activation by Prog. Conclusion: Activation of the AR by clinically relevant levels of Preg and Prog accumulating in abiraterone‐treated patients may act as a driver for CRPC. These data provide a scientific rationale for combining CYP17A1 inhibitors with antiandrogens, particularly in patients with overexpressed or mutated‐AR

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. [14C]-docetaxel and [14C]-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

Safety of optical coherence tomography in daily practice: a comparison with intravascular ultrasound

Previous studies have reported the safety and feasibility of both time-domain optical coherence tomography (TD-OCT) and Fourier-domain OCT (FD-OCT) in highly selected patients and clinical settings. However, the generalizability of these data is limited, and data in unselected patient populations reflecting a routine cathlab practice are lacking. We compared safety of intracoronary FD-OCT imaging to intravascular ultrasound (IVUS) imaging in a large real-world series of consecutive patients who underwent invasive imaging during coronary catheterization in our centre. This is a prospective, single-centre registry of patients scheduled for coronary angiography or intervention undergoing intracoronary imaging with FD-OCT or IVUS between April 2008 and December 2013. Intra-procedural and major in-hospital adverse events that could be possibly related to invasive imaging were registered routinely by the operator as part of our clinical report and prospectively recorded in our database. These events were retrospectively individually adjudicated by an independent safety committee. Between April 2008 and December 2013, 13 418 diagnostic or interventional coronary catheterization procedures were performed. Of these, 1142 procedures used OCT and 2476 procedures used IVUS. Invasive imaging-related complications were rare, did not differ between the two imaging methods (OCT: n = 7, 0.6%; IVUS: n = 12, 0.5%; P = 0.6), and were self-limiting after retrieval of the imaging catheter or easily treatable in the catheterization laboratory. No major adverse events, prolongation of hospital stay, or permanent patient harm was observed. FD-OCT is safe in an unselected and heterogeneous group of patients with varying clinical settings