Docetaxel-related toxicity in metastatic hormone-sensitive and metastatic castration-resistant prostate cancer

Docetaxel plus androgen deprivation therapy (ADT) offers a survival benefit in metastatic hormone-sensitive prostate cancer (mHSPC). However, one trial evaluating docetaxel in mHSPC (GETUG-AFU15) showed unexpected toxicity; raising concerns that docetaxel may carry increased toxicity when used to treat mHSPC compared to metastatic castration-resistant prostate cancer (mCRPC). We conducted a retrospective analysis evaluating differences in toxicity based on the clinical state (i.e., mHSPC vs. mCRPC) that docetaxel was used. Patients initiating docetaxel between 1/1/2014 and 7/15/2015 were included, with the former date chosen to coincide with the press release for the first mHSPC study that showed a survival benefit with early docetaxel; ensuring contemporary docetaxel-treated cohorts. Thirty-nine mCRPC and 22 mHSPC patients were included. Compared to mCRPC, mHSPC patients were younger (median years: 66.3 vs. 71.8, P = 0.007); had better performance status (ECOG 0-1: 100 vs. 62 %, P < 0.0001); and used opiates less frequently (29 vs. 66 %, P = 0.04). Neutropenic fevers occurred in 9 and 5 % (P = 0.95) of men with mHSPC and mCRPC, respectively. Other toxicities also occurred at similar rates between cohorts. The incidence of any toxic event was 73 and 67 % (P = 0.84) for men with mHSPC and mCRPC, respectively. Within the mHSPC cohort, neutropenic fevers occurred at a similar rate regardless of the time interval between initiating ADT and the start of docetaxel. We did not observe a significant difference in toxicity between mHSPC and mCRPC patients receiving docetaxel. However, the small sample size and retrospective nature of this study limit our ability to draw definitive conclusions.     

Novel treatment options in the management of metastatic castration-naïve prostate cancer; which treatment modality to choose?

Androgen-deprivation therapy (ADT) has been the mainstay of treatment of metastatic prostate cancer since the first report of its hormonal dependence in the 1940s. Since 2015, the addition of docetaxel and the addition of abiraterone to ADT have conferred substantial overall survival benefit in men with metastatic castration-naïve prostate cancer (mCNPC). The shift of these treatment options for metastatic prostate cancer from the castration-resistant setting to the castration-naïve setting has led to new challenges in the management of this disease. It remains to be determined which patients may benefit most from either early concomitant docetaxel or from abiraterone with ADT, since biomarkers for early therapy response and risk stratification are currently lacking. Therefore, the ability to personalize medicine is hampered. Furthermore, the earlier detection of metastatic prostate cancer by using new imaging modalities makes the application of clinical trial results in daily practice increasingly challenging. Recently, both local radiotherapy to the primary tumor combined with ADT and abiraterone combined with ADT showed a survival benefit in low-volume disease patients. The latest data also demonstrated a survival benefit with the addition of apalutamide or enzalutamide to ADT. The extent of metastatic disease may become one of the most important factors to determine treatment choice. In this review article, we summarize trial data to provide guidance for treatment selection in metastatic castration-naïve prostate cancer.     

Recent trend of androgen deprivation therapy in newly diagnosed prostate cancer patients: Comparing between high- and middle-income Asian countries

The number of newly diagnosed prostate cancer cases varies across Asia, with higher mortality-to-incidence ratio reported in developing nations. Androgen deprivation therapy (ADT), alone or in combination, remains the mainstay of first-line treatment for advanced prostate cancer. Key findings of extensive research and randomized controlled trials have shaped current clinical practice and influenced clinical guideline recommendations. We describe here the recent trend of ADT in newly diagnosed prostate cancer for Asia focusing on Japan (high-income country) and Malaysia (middle-income country) based on the Asian Prostate Cancer (A-CaP) Study. The combination of radiotherapy and ADT or ADT alone was common in patients with intermediate-to-high risk localized and locally advanced disease. For metastatic prostate cancer, maximum androgen blockade (gonadotrophin-releasing hormone [GnRH] agonist/antagonist plus antiandrogen) was prevalent among the Japanese patients while primary ADT alone with GnRH agonist/antagonist was widely practiced in the Malaysian cohort. Upfront combined therapy (ADT plus docetaxel or androgen receptor pathway inhibitor) has significantly improved the outcomes of patients with metastatic castration-naïve prostate cancer. Its application, however, remains low in our cohorts due to patients’ financial capacity and national health insurance coverage. Early detection remains the cornerstone in prostate cancer control to improve treatment outcome and patient survival.     

Should docetaxel be standard of care for patients with metastatic hormone-sensitive prostate cancer? Pro and contra

Following the results of the TAX-327 study, questions have been raised as to whether administering chemotherapy to men with prostate cancer before symptomatic disease progression when receiving standard hormonal treatment can improve the duration and quality of patient survival. The GETUG-AFU-15 and CHAARTED studies both assessed the efficacy and tolerability of androgen deprivation therapy (ADT) with or without docetaxel in men with metastatic hormone-naive prostate cancer. Both studies included a mix of patients with de novo metastatic disease (∼75%) and patients who developed metastases following treatment of localized disease. A short course of ADT was allowed in both trials prior to accrual. Key differences between the two studies include the number of patients with high-volume metastases (GETUG-AFU-15: 52%; CHAARTED: 65%) and number of docetaxel cycles (GETUG-AFU-15: up to nine cycles; CHAARTED six cycles). Both studies reported an improvement in progression-free survival with docetaxel plus ADT versus ADT alone. The GETUG-AFU-15 did not find a significant difference in the primary end point of overall survival (OS) {hazard ratio (HR) 0.9 [95% confidence interval (CI) 0.7–1.2]; P = 0.44} for ADT plus docetaxel versus ADT alone. The CHAARTED study met the primary end point of OS [HR 0.61 (95% CI 0.47–0.80); P = 0.0003], and in a subset analysis reported the greatest improvement in OS for patients with high-volume disease [HR 0.60 (95% CI 0.45–0.81); P = 0.0006]. The following article debates the results from the GETUG-AFU-15 and CHAARTED studies and asks whether medical practice should be changed for patients with metastatic hormone-naive prostate cancer based on the results of one positive study.     

Cost-effectiveness Analysis of Innovative Therapy for Patients with Newly Diagnosed Hormone-Sensitive Metastatic Prostate Cancer

BackgroundThe optimal therapeutic strategies for patients with metastatic hormone-sensitive prostate cancer (mHSPC) followed by metastatic castrate-resistant prostate cancer (mCRPC), in terms of cost and effectiveness, remains unknown. This study aims to compare the cost-effectiveness of various potential strategies, from the start of first-line treatment in mHSPC to the death of the patients.MethodsTwo Markov decision-analysis models were developed, one for cohort A “asymptomatic/mildly symptomatic patients in mCRPC”, and one for cohort B “symptomatic patients in mCRPC”. Each strategy reflects daily practice for mHSPC until progression in mCRPC from the start of first treatment regimen with either docetaxel or abiraterone acetate plus prednisone (AA) in mHSPC to the death of the patient. The cost-effectiveness analysis was performed from the French public health care system perspective. Only direct medical costs were included. Survival data were extracted from results of published randomized clinical trials.ResultsFor cohort A, docetaxel followed by AA is the most cost-effective therapeutic strategy (€96,925 for 4.24 life-years). For cohort B, docetaxel followed by docetaxel is the most cost-effective therapeutic strategy (€81,463 for 4.05 life-years). Sensitivity analyses confirmed the robustness of our results except for a price reduction of 70% for AA or enzalutamide.ConclusionOur approach is innovative to the extent that our analysis considers various potential strategies for metastatic prostate cancer (mPC). Our economic evaluation suggests that a price reduction of AA or enzalutamide impacts on the results. This approach must continue, including new drugs for patients with mPC.     

Clinical implications for a treatment algorithm and differential indication to hormone therapy and chemotherapy options in metastatic castrate-resistant prostate cancer: a personal view

Although docetaxel is still considered a mainstay of treatment in metastatic castrate-resistant prostate cancer (mCRPC), in the last few years, new agents have been developed to improve survival in this setting and reach a possible optimal personalized treatment strategy. In this paper, we provide a personal view and an algorithm for mCRPC patients, according to available evidence, personal opinion and experience. Abiratone acetate, cabazitaxel, radium-223, sipuleucel-T and enzalutamide, together with docetaxel, have demonstrated a survival benefit in these patients. The use of rechallenge with docetaxel in mCRPC patients with disease progression after a first response has been considered. These new agents complicated the scenario and posed the challenge to move from the old sequential to a new algorithm-based approach. At this stage, the algorithm is necessarily based on experts’ opinion, since the efficacy of a single agent in a specific setting has not been validated by sequential trials.     

Clinical Outcomes of First-line Abiraterone Acetate or Enzalutamide for Metastatic Castration-resistant Prostate Cancer After Androgen Deprivation Therapy + Docetaxel or ADT Alone for Metastatic Hormone-sensitive Prostate Cancer

Background

The CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials showed that the addition of docetaxel (D) to androgen deprivation therapy (ADT) prolonged longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of upfront D on subsequent therapies is still unexplored. As abiraterone acetate (AA) and enzalutamide (E) are the most commonly used first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), we aimed to assess whether they maintained their efficacy after ADT+D versus ADT alone.

Beyond Frontline Therapy with Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer: A Real-World US Study

BackgroundReal-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting.MethodsAdults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013–03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis.ResultsAmong 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively.ConclusionsThis real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.     

Is there still a place for docetaxel rechallenge in prostate cancer?

Three-weekly docetaxel plus prednisone is the standard first-line cytotoxic treatment for patients with metastatic castrate-resistant prostate cancer (mCRPC). Today, several new treatment options are available for patients with tumor progression after first-line docetaxel: Abiraterone, enzalutamide, cabazitaxel, sipuleucel-T immunotherapy, and the radionuclide radium-223. However, despite the evolving scenario in CRPC treatment, the optimal sequencing of the innovative therapies remains unclear. The reintroduction of docetaxel at the occurrence of disease progression after a drug holiday (docetaxel rechallenge) was often proposed, and this chemotherapeutic agent showed to maintain antitumor activity in mCRPC patients. Docetaxel rechallenge may still constitute a valid treatment option mainly for patients with favorable response to first-line docetaxel, at least > 3 mo progression-free interval, age less than 75 years, good performance status, and acceptable docetaxel toxicity. The risk of cumulative toxicity must be evaluated, since sensory neuropathy, nail disorders and fatigue might occur on docetaxel rechallenge.     

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel,Cabazitaxel, and Androgen Receptor–Targeted Agents

Background

Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor–targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).

Impact of prior androgen receptor-axis-targeted agents on the clinical activity of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer: comparative assessment between abiraterone acetate and enzalutamide

The objective of this study was to investigate the impact of prior treatment with androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate (AA) and enzalutamide (Enz), on the activity of subsequently introduced docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 114 mCRPC patients consisting of 54 and 60 who progressed following treatment with AA and Enz, respectively, prior to the introduction of docetaxel, and compared oncological outcomes with docetaxel between these two groups. There were no significant differences in the major clinicopathological characteristics before treatment with docetaxel between the AA and Enz groups. The prostate-specific antigen (PSA) response rates to docetaxel in the AA and Enz groups were 40.7 and 43.3%, respectively, with no significant differences in the rates between these two groups. Following the introduction of docetaxel, the median PSA progression-free survival (PFS) and overall survival (OS) in the 114 patients were 7.2 and 17.5 months, respectively. There was no significant difference in the PSA PFS or OS between the AA and Enz groups. Despite the lack of a significant impact of the type of ARAT agent on PSA PFS or OS by univariate analysis, multivariate analyses identified the following independent prognostic predictors: performance status (PS) for PSA PFS and PS and visceral metastasis for OS. Collectively, these findings suggest that the type of ARAT agent may not have a significant impact on disease control by subsequent docetaxel therapy in mCRPC patients.     

Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials

The derived neutrophil-to-lymphocyte ratio (dNLR) was prognostic for survival in men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy in two randomized phase III trials. A high dNLR (≥2) was associated with shorter survival irrespective of the received treatment. This readily available biomarker may serve for risk stratification in future clinical trials.BackgroundThe neutrophil-to-lymphocyte ratio (NLR), a marker of host inflammation, has been associated with poor outcome in several solid tumors. Here, we investigated associations of the derived NLR (dNLR) and duration of initial androgen deprivation therapy (ADT) with survival of men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy.Patients and methodsData from the multinational randomized phase III studies VENICE and TAX327 included a total of 2230 men with mCRPC randomized to receive first-line chemotherapy, and were used as training and validation sets, respectively. Associations of dNLR and duration of initial ADT with overall survival (OS) were evaluated by multivariable Cox regression analysis in the training set stratified for performance status and treatment arm. The model was then tested in the validation set. Subsequently, we investigated the treatment effect of docetaxel on OS in subgroups according to dNLR and duration of initial ADT.ResultsIn the training set, both dNLR ≥median (2) and duration of initial ADT <median (15 months) were associated with increased risk of death [hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.11–1.50,P < 0.001 and HR 1.41; 95% CI 1.21–1.64,P < 0.001, respectively] after adjustment for age, alkaline phosphatase, hemoglobin, and pain at baseline. In the validation set, dNLR remained an independent prognostic factor for OS (HR 1.43; 95% CI 1.20–1.70,P < 0.001), whereas duration of initial ADT was not (HR 1.16; 95% CI 0.97–1.37,P = 0.10). In subgroup analyses of the TAX327 study, docetaxel improved OS irrespective of dNLR and duration of initial ADT.ConclusionThe dNLR was prognostic for OS in men with mCRPC receiving first-line chemotherapy in two randomized phase III trials. A high dNLR (≥2) was associated with shorter survival irrespective of the received treatment. This readily available biomarker may serve for risk stratification in future clinical trials and could be incorporated into prognostic nomograms.Clinical Trials numberNCT00519285.     

No significant impact of prior treatment profile with docetaxel on the efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer

The objective of this study was to retrospectively analyze the oncological outcomes of Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel. This study included a total of 63 consecutive Japanese mCRPC patients treated with cabazitaxel following the failure of docetaxel, and assessed the prognostic significance of cabazitaxel therapy in these patients focusing on the association of efficacies between two taxane agents. After treatment with cabazitaxel (median 5 cycles), prostate-specific antigen (PSA) decline was observed in 39 patients (61.9%), including 13 (27.0%) achieving the response defined by PSA decline ≥50%. The median progression-free survival (PFS) and overall survival (OS) periods after the introduction of cabazitaxel were 4.1 and 14.8 months, respectively. The response rate to cabazitaxel was not significantly different between responders and non-responders to prior docetaxel, and there was no significant correlation between the PFSs with docetaxel and cabazitaxel. Furthermore, univariate analyses of several parameters identified the performance status (PS) and clinical symptoms, but not the cycles of docetaxel therapy, total amount of administered docetaxel or objective response to docetaxel therapy, as significant predictors of OS on cabazitaxel therapy, of which only PS was independently associated with OS on multivariate analysis. These findings suggest that oncological outcomes in Japanese mCRPC patients receiving cabazitaxel are generally satisfactory, irrespective of the profiles related to prior treatment with docetaxel, and that it might be preferable to introduce cabazitaxel to mCRPC patients with a good PS to maximize the prognostic benefit of this agent.     

Piecing the puzzle together: Docetaxel cycles and current considerations in the treatment of metastatic castration-resistant prostate cancer

Docetaxel is the current first line therapy for metastatic castration-resistant prostate cancer (mCRPC), but there is no standard number of docetaxel cycles given to patients. In their post hoc analysis of the Mainsail study, de Morrée et al. show that the number of docetaxel cycles administered to a patient is a significant factor contributing to overall survival. These findings warrant further investigation into the standardization of the number of docetaxel cycles administered.     

TROPIC: Phase III trial of cabazitaxel for the treatment of metastatic castration-resistant prostate cancer

For patients with metastatic castration-resistant prostate cancer (mCRPC), the current standard of care is chemotherapy involving the tubulin-binding taxane docetaxel. However, as the tumor cells become resistant to docetaxel-based therapy, disease progression is inevitable, and until recently there was no further available treatment beyond palliative care. In June 2010, cabazitaxel, a next-generation taxane, was approved by the US FDA for the treatment of mCRPC that has progressed after docetaxel therapy. This article describes the background and rationale of cabazitaxel's development and the clinical study program that led to its FDA approval, focusing on the Phase III TROPIC trial that demonstrated the efficacy of cabazitaxel plus prednisone in the treatment of mCRPC. Future development of this therapy and others under investigation is discussed.     

Das metastasierte Prostatakarzinom: Grundlagen der Therapie im Jahr 2013

Background

Androgen deprivation (orchiectomy or LHRH analogue) is the standard first line treatment for metastatic prostate cancer. In case of progression (metastatic castration-resistant prostate cancer, mCRPC), further treatment was restricted to chemotherapy with docetaxel. This cytotoxic drug was the only one to demonstrate a significant overall survival benefit and improve symptom control.

Objective

Within the last few years five new treatments for patients with mCRCP have reached a significant overall survival benefit in large phase III trials.

Material and Methods

Interestingly they have different mechanisms of action: abiraterone blocks testosterone synthesis, enzalutamide inhibits the function of the androgen receptor, cabazitaxel is a cytotoxic drug, radium-223 is a radionuclide (alpha-emitter) and sipuleucel-T stimulates the patient’s immune system.

Results

It is currently unclear in which sequence or combinations these drugs should be best used. Answering this question as well as integrating further new treatments will be the major challenge for the coming years.     

Résistance au docétaxel: mécanismes et applications thérapeutiques

Docetaxel is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients, but its effectiveness is limited in time and tumor escape the inevitable. The various combinations with docetaxel were negative in terms of prolongation of overall survival. A better understanding of mechanisms of docetaxel resistance on microtubule and p-glycoprotein, for instance, would guide the therapeutic strategy. After the administration of docetaxel, cabazitaxel, abiraterone, alpharadin and recently MDV3100 have shown their effectiveness in improving overall survival compared to a placebo or mitoxantrone in phase III trials. Also in predocetaxel stage, sipuleucel-T has proven effective in asymptomatic mCRPC patients. The identification of predictors of response to taxanes will personalize chemotherapy to induce durable response and significantly prolonged survival.     

Therapy of Advanced Prostate Cancer: Targeting the Androgen Receptor Axis in Earlier Lines of Treatment

With the decrease in PSA screening based on the 2011 United States Preventive Services Task Force guidelines and the potential approval of highly sensitive imaging techniques over the next few years, we are likely to see an increasing trend of metastatic prostate cancer diagnosis. Traditional therapy for nonmetastatic prostate cancer (nmPC) has consisted of androgen deprivation therapy (ADT) followed by other hormonal therapy maneuvers, such as anti-androgen withdrawal, herbal preparations, low dose steroids, or ketoconazole. Androgen receptor-axis-targeted therapies (ARAT) were previously only approved for patients with metastatic castration resistant prostate cancer (mCRPC). This has recently changed after reporting of results from the SPARTAN and PROSPER trials, which were conducted in nonmetastatic CRPC (nmCRPC) patients. These studies demonstrated improved metastasis-free survival with apalutamide and enzalutamide, each compared to placebo in a double blind randomized setting. In 2017, the LATITUDE and STAMPEDE studies demonstrated marked survival benefit with early abiraterone and prednisone in patients with metastatic hormone sensitive prostate cancer (mHSPC) in addition to ADT. Other second-generation AR antagonists are currently in phase 3 trials in mHSPC and nmCRPC. This article summarizes the key clinical trials that led to FDA approval of ARAT in the mHSPC and nmCRPC settings and highlights potential limitations, future directions, and treatment-algorithms when selecting patients for early therapy in mHSPC and NMPC.     

Enzalutamide,modalités pratiques d’utilisation d’une nouvelle hormonothérapie

Enzalutamide (MDV3100) is a non-steroidal antiandrogen of second generation that has shown efficacy in metastatic castration-resistant prostate cancer (mCRPC). The study AFFIRM demonstrated a statistically significant increase in overall survival among patients who have progressed following a docetaxel chemotherapy. Based on these results, a marketing authorization for enzalutamide has been granted. The enzalutamide has been shown to be generally well tolerated. Other trials are underway to evaluate its earlier use in the management of mCRPC. A pivotal registration phase III study (PREVAIL) is ongoing to investigate the effectiveness of enzalutamide in patients who have not yet received chemotherapy.     

Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer

IntroductionTreatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1]. In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds.MethodsTo identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation.ResultsWe observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide.ConclusionsIn conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.