Robert J. van Soest

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.

Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation

Resistance to docetaxel is common in metastatic castration‐resistant prostate cancer (mCRPC) and may be caused by sub‐therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in docetaxel‐pretreated and docetaxel‐refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of docetaxel following treatment with novel androgen receptor (AR)‐targeted agents, we also investigated taxane efficacy in an enzalutamide‐resistant tumor model.

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.

The Natural History and Outcome Predictors of Metastatic Castration-resistant Prostate Cancer

CONTEXT Biomarkers for the treatment of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed by clinicians to facilitate treatment decisions. OBJECTIVE To review current prognostic and predictive biomarkers in mCRPC. EVIDENCE ACQUISITION We performed a nonsystematic review of the literature from 2004 to August 2016 by searching in Medline. Cross-matching references were used to search for additional articles. We reviewed clinical research and review articles written in the English language. EVIDENCE SYNTHESIS Nomograms of prognostic factors (eg, albumin, lactate dehydrogenase) enable clinicians to estimate the prognosis of men with mCRPC. These prognostic tools may aid with when to trigger treatment, therapeutic monitoring, and follow-up. However, validated predictive biomarkers in mCRPC are still lacking. Androgen receptor (AR) splice variants (ie, AR-V7), gene fusions, and point mutations determined using liquid biopsies such as circulating tumor cells (CTCs) or cell-free DNA (cfDNA) are promising biomarkers that are the subject of ongoing research. Patient biomarkers (eg, neutrophil-to-lymphocyte ratio) are readily available and come with no extra cost but need further validation before their implementation in clinical practice. CONCLUSIONS Determination of AR-V7 in CTCs is a big step towards a more personalized treatment approach in mCRPC. Genomic characterization of liquid biopsies such as CTCs, cfDNA, and circulating RNA are noninvasive tools to further personalize treatment in prostate cancer. Clinical parameters are readily available, but are derived from retrospective studies and should be interpreted with care. Only by conducting biomarker-driven studies, rather than large one-size-fits-all trials, will we be able to improve prostate cancer treatment. PATIENT SUMMARY Several biomarkers are currently under investigation that may predict which patients will respond to specific therapies in the future of metastatic castration-resistant prostate cancer treatment.

Re: Nader Al Nakouzi, Sylvestre Le Moulec, Laurence Albigès, et al. Cabazitaxel Remains Active in Patients Progressing After Docetaxel Followed by Novel Androgen Receptor Pathway Targeted Therapies. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.04.015

We have read with interest the article by Al Nakouzi et al. on the efficacy of cabazitaxel after prior treatment with novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide [1]. The authors report that cabazitaxel remains effective as second-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC), even after treatment with these hormonal agents. This is a clinically relevant observation, since recent retrospective studies suggested that docetaxel efficacy is less well sustained following abiraterone treatment [2]. We and others have recently reported that both docetaxel and cabazitaxel share an overlapping working mechanism with either abiraterone and enzalutamide by inhibiting AR nuclear translocation, which potentially confers crossresistance [2–4]. In the present paper, the authors came to a different conclusion, since no clinical evidence of reduced cabazitaxel activity after prior abiraterone exposure was observed. Preclinical data were presented that might suggest that cabazitaxel activity is not mainly mediated through AR inhibition. However, several limitations in the methodology may limit their conclusions. First, from a clinical and scientific perspective, a direct comparison of cabazitaxel with docetaxel is essential. If the lack of cross-resistance for cabazitaxel could be explained by its less AR-dependent effect, this should not be the case for docetaxel, for which cross-resistance with abiraterone has been suggested in clinical reports and a preclinical study by our group [2,4]. Unfortunately, in the present study, no data for docetaxel or other cytotoxic controls were provided in the AR-transport and proliferation assays, which limits the value of their conclusions [1]. Second, the cabazitaxel dose (10 nM) used may have been too low to fully inhibit AR transport [1]. Studies on microtubule dynamics have demonstrated that taxanes suppress dynamic instability of microtubules at low dose but alter microtubule polymer mass at high concentrations ( 100 nM) [5]. A similarly high concentration, which can be

The initial biopsy Gleason score as a predictive marker for docetaxel survival benefit in patients with prostate cancer: Data from the TAX 327 study.

44 Background: The TAX 327 study was conducted in 1,006 men with metastatic castration-resistant prostate cancer (mCRPC) who were randomized to receive 3-weekly docetaxel (D3), weekly docetaxel (D1) or 3-weekly mitoxantrone (M), each with prednisone. Survival and symptom control were superior following D3 as compared to M. In this post-hoc analysis we aimed to identify factors that could characterize subgroups of patients who obtained the greatest benefit from the use of D3 as compared to M. METHODS The TAX 327 database was used to investigate if patients with poorly differentiated tumors (Gleason 7-10) at diagnosis had greater benefit from D3 as compared to M, than patients with better differentiated tumors (Gleason ≤6). Using a Cox model, we compared overall survival (OS) between the treatment groups within each subgroup of Gleason score. RESULTS Baseline characteristics known to predict OS including visceral metastasis and time from first hormonal treatment to the start of chemotherapy were well balanced between patient groups, except for an imbalance in the small group of patients with impaired Karnofsky performance score (PS) (see table). The TAX 327 data showed that the OS benefit of D3 versus M is greater in patients with high grade tumors (median OS 18.9 vs 14.5 months) than in patients with low grade tumors (median OS 21.6 vs 20.7 months). CONCLUSIONS The survival benefit obtained with docetaxel as compared to mitoxantrone is greater in patients with high Gleason score tumors. Although this finding is hypothesis-generating and needs confirmation in other trials, it may provide additional guidance in treatment decisions regarding the use of chemotherapy as first line treatment for patients with mCRPC. [Table: see text].

Cell-free DNA in Advanced Prostate Cancer: A Biomarker Revolution Under Way?

The treatment armamentarium for metastatic castrationresistant prostate cancer (mCRPC) has significantly expanded over the past years with the introduction of several new approved drugs including cabazitaxel, abiraterone, enzalutamide, sipuleucel-T, and radium-223 [1]. Despite these advances, no predictive biomarkers for benefit from these treatment options exist, hampering a personalized treatment approach. Cell-free DNA (cfDNA) is DNA derived from apoptotic cells that can be detected in peripheral blood. cfDNA consists of both tumor DNA (ctDNA) and nonmalignant DNA, which is mostly derived from hematopoietic cells. Although the majority of the cfDNA fraction comes from nonmalignant cells, the fraction of ctDNA is highly variable, and generally increases in patients with more advanced disease, reflecting a greater disease burden. The representation of metastases by ctDNA was demonstrated in a recent study in men with mCRPC showing that the mutational load in ctDNA strongly correlated with that of metastatic tumor biopsies [2]. Since the half-life of ctDNA is relatively short (<2 h) it might thus provide a real-time snapshot of the tumor status. These promising data suggest that cfDNA can provide a noninvasive liquid biopsy for both quantitative and qualitative tumor assessments, potentially guiding a personalized treatment approach. In this light, it has been shown that high levels of ctDNA are associated with shorter progression-free survival (PFS) and overall survival (OS) in men with mCRPC [3,4]. In this issue of European Urology, Mehra and colleagues [5] report on results from a prospective collection of cfDNA

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.

Re: Johann S. de Bono, Matthew R. Smith, Fred Saad, et al. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2016.06.033

We read with interest the article by de Bono et al [1] reporting on the efficacy of subsequent chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC) after treatment with abiraterone acetate (AA) in the COU-AA-302 trial. This article addresses a very important question, since cross-resistance between AA and docetaxel chemotherapy has been suggested in preclinical and retrospective clinical studies [2,3]. In 2012 Dr. de Bono and his team were the first to hypothesize cross-resistance between these drugs reporting a 50% prostate-specific antigen (PSA) response rate (RR) of 26% in men who received docetaxel after prior treatment with AA, which was notably lower than anticipated [2]. Comparable findings were reported by investigators from the Johns Hopkins Institute [3]. In the current paper, a similar modest PSA RR of 27% (confirmed), and 40% (unconfirmed) was obtained, which led the authors to the unexpected conclusion that docetaxel has meaningful antitumor activity after treatment with AA. Of note, the PSA response data in both studies [1,2] were compared to the historical control group of the TAX327 trial of docetaxel in abiraterone-naı̈ve men, which reported a PSA RR of 45%. However, more contemporary data on mCRPC patients treated with docetaxel as first-line treatment in the context of phase 3 trials have been published, which showed confirmed PSA RRs in the range of 58–64% [4,5]. In this light, a confirmed PSA RR of 27% in the current paper versus 58–64% in two contemporary cohorts of men treated with docetaxel might only be confirmatory data indicating that the efficacy of docetaxel indeed may be affected by prior AA treatment. To date, strong evidence has been hampered by the use of historical control groups, which obviously limits direct comparison of data. A valid comparison on the efficacy of docetaxel among men who received prior AA can only be conducted against a control arm of men with similar patient