cabazitaxel and Prostatic-Neoplasms--Castration-Resistant

Cabazitaxel is an effective treatment of post-docetaxel metastatic castration-resistant prostate cancer (mCRPC). We aimed to assess the sequencing impact and identify prognostic factors of oncologic outcomes in mCRPC patients treated with cabazitaxel.. PUBMED, Web of Science, and Scopus databases were searched for articles published before January 2022 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Studies were deemed eligible if they investigated pretreatment clinical or hematological prognostic factors of overall survival (OS) in mCRPC patients with progression after docetaxel treated with available treatments including cabazitaxel.. Overall, 22 studies were eligible for the meta-analysis. In mCRPC patients treated with docetaxel, subsequent treatment with cabazitaxel was associated with better OS compared to that without cabazitaxel (pooled hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.56-0.89). Among the patients treated with cabazitaxel, several pretreatment clinical features and hematologic biomarkers were associated with worse OS as follows: poor performance status (PS) (pooled HR: 1.92, 95% CI: 1.33-2.77), presence of visceral metastasis (pooled HR: 2.13, 95% CI: 1.62-2.81), symptomatic disease (pooled HR: 1.47, 95% CI: 1.25-1.73), high PSA (pooled HR: 1.76, 95% CI: 1.27-2.44), high alkaline phosphatase (ALP) (pooled HR: 1.45, 95% CI: 1.28-1.65), high lactate dehydrogenase (LDH) (pooled HR: 1.54, 95% CI: 1.00-2.38), high c-reactive protein (CRP) (pooled HR: 4.40, 95% CI: 1.52-12.72), low albumin (pooled HR:1.09, 95% CI: 1.05-1.12) and low hemoglobin (pooled HR:1.55, 95% CI: 1.20-1.99).. Sequential therapy with cabazitaxel significantly improves OS in post-docetaxel mCRPC patients. In mCRPC patients treated with cabazitaxel, patients with poor PS, visceral metastasis, and symptomatic disease were associated with worse OS. Further, pretreatment high PSA, ALP, LDH or CRP as well as low hemoglobin or albumin, were blood-based prognostic factors for OS. These findings might help guide the clinical decision-making for the use of cabazitaxel and prognostication of its OS benefit.

Topics: Docetaxel; Hemoglobins; Humans; Male; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Taxanes have been used as monotherapy for metastatic prostate cancer for two decades.. The current status of docetaxel and cabazitaxel in the treatment sequence for metastatic prostate cancer needs to be clarified.. Overview of the existing literature regarding approval, dosage and new combination options for metastatic castration-resistant prostate cancer (mCRPC).. Taxanes represent one, but no longer the only treatment option for mCRPC. Previously, monotherapy was standard of care in the first and second line for mCRPC; nowadays taxanes are thrusted in the background due to new encouraging drug options. Based on the promising data of docetaxel in triple therapy setting for hormone-sensitive stage, its role as monotherapy in mCRPC needs to be clarified. Cabazitaxel is an alternative to PSMA radioligand therapy after failure of novel hormonal therapy (NHT) and docetaxel. Therapy adherence for taxanes can be significantly improved by dosage adjustments. Both treatment-related neuroendocrine prostate cancer (t-NEPC) and aggressive variant of prostate cancer (AVPC) represent a challenge for experienced uro-oncologists. Here, the combination of taxane plus platinum represents a promising option.. Taxanes are indicated in different stages of metastatic prostate cancer. Their use, particularly in combination with other drugs, appears to be promising. Traditional sequential taxane monotherapy regimens will be challenged by novel systemic therapy approaches.. HINTERGRUND: Seit 2 Jahrzehnten werden Taxane in der Monotherapie des metastasierten Prostatakarzinoms eingesetzt.. Es gilt den Stellenwert von Docetaxel und Cabazitaxel in der Therapiesequenz des metastasierten Prostatakarzinoms zu klären.. Der Beitrag gibt eine Übersicht der vorhandenen Literatur bezüglich Zulassung, Dosierung und neuer Therapieoptionen beim metastasierten kastrationsresistenten Prostatakarzinom (mCRPC).. Taxane stellen eine, aber nicht mehr DIE Therapieoption beim mCRPC dar. Vormals DER Standard als Monotherapie in der Erst- und Zweitlinie bei mCRPC, stehen Taxane aufgrund neuer vielversprechender Medikamentenoptionen nicht mehr im primären Vordergrund. Aufgrund der Einsatzmöglichkeit von Docetaxel im hormonsensitiven Stadium gilt es, seinen sinnvollen Einsatz als Monotherapie beim mCRPC zu klären. Cabazitaxel ist eine Alternative zur PSMA-Radioligandentherapie („prostate-specific membrane antigen“) nach Versagen von NHT (neue hormonelle Therapie) und Docetaxel. Durch Anpassung der Medikamentendosis an die Komorbiditäten des mCRPC-Patienten kann die Therapieakzeptanz deutlich verbessert werden. Sowohl das behandlungsinduzierte neuroendokrine Prostatakarzinom (t-NEPC) als auch die aggressiven Prostatakarzinomvarianten (AVPC) stellen eine Herausforderung für erfahrene Uroonkolog*innen dar. Hier ist die Kombination aus Taxan plus Platinderivat eine vielversprechende Option.. Taxane haben ihre Indikation in verschiedenen Stadien des metastasierten Prostatakarzinoms. Ihr Einsatz insbesondere in Kombination mit anderen Substanzklassen erscheint vielversprechend. Traditionelle sequenzielle Monotherapieschemata der Taxane müssen durch neuartige Systemtherapieansätze hinterfragt werden.

Topics: Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

For post-docetaxel treatment of metastatic castrate-resistant prostate cancer (mCRPC), cabazitaxel has demonstrated superior third line PFS and OS compared to androgen receptor pathway inhibitors (ARPIs) in patients who progress within 12 months on first ARPI. The impact of first ARPI response, in particular responses beyond 12 months, on cabazitaxel outcomes in real-world populations is uncertain, as are other factors impacting cabazitaxel use.. mCRPC patients in Alberta, Canada who received docetaxel from October 1, 2012 to December 31, 2017 were included. We reviewed mCRPC therapies, correlating cabazitaxel use with patient characteristics and TROPIC trial inclusion/exclusion criteria. OS and PFS were evaluated in patients who received cabazitaxel, stratified by time to progression on first ARPI ≤ 12 months (poor ARPI responders, PAR) or >12 months (strong ARPI responders, SAR), using the Kaplan-Meier method.. PAR patients had inferior OS compared to SAR patients (12.3 vs. 24.8 months, P < .001). OS was longer in PAR patients receiving cabazitaxel compared to those not treated with cabazitaxel (16.9 vs. 10.3 months, P = .015), but this benefit was not seen in the SAR group (17.1 vs. 32 months, P = .084). Cabazitaxel use was associated with reduced PFS first line post-docetaxel in SAR (3.5 vs. 14.7 months, P < .001) but not PAR patients. Of 592 patients, 170 (29%) received cabazitaxel post-docetaxel, compared to 280 (47%) and 250 (42%) for abiraterone and enzalutamide. 238 patients (40%) did not have a discussion of cabazitaxel documented. Cabazitaxel use was increased in patients who fit TROPIC trial criteria (P < .001).. In a real-world mCRPC cohort, cabazitaxel use was associated with longer OS among PAR patients, but crucially not among strong ARPI responders. Cabazitaxel was used less frequently and later than ARPIs post-docetaxel. These data help support first ARPI progression time as a consideration in treatment sequencing.

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

Cabazitaxel (25 mg/m

Topics: Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Filgrastim; Follow-Up Studies; Humans; Leukopenia; Male; Neutropenia; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids

Recent population-based studies suggest that the incidence of advanced and metastatic prostate cancer may be increasing. Concurrently with this apparent stage migration toward advanced disease, several major developments have occurred in the treatment paradigm for men with advanced prostate cancer. These include the US Food and Drug Administration approval of 8 novel agents over the last decade. In addition to novel pharmaceuticals, rapidly evolving diagnostic tools have emerged. This review provides a primer for clinicians who treat men with advanced prostate cancer, including medical oncologists, radiation oncologists, and urologists.

Topics: Adenocarcinoma; Androstenes; Benzamides; Clinical Trials as Topic; Combined Modality Therapy; Diagnostic Imaging; Disease Management; Docetaxel; Humans; Male; Multicenter Studies as Topic; Nitriles; Phenylthiohydantoin; Precision Medicine; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radiotherapy, Adjuvant; Radium; Taxoids; Therapies, Investigational

Indications for chemotherapy have increased in prostate cancer (PCA), many of which are shared with new hormonal agents (NHA). With no head to head comparison available, defining the optimal sequence and identifying biomarkers to predict response, has been a focus of intense research in PCA. We aim to summarize the best currently available evidence in all stages of disease to help guide therapy.. In metastatic castration-resistant prostate cancer, Cabazitaxel has shown improved radiographic progression-free survival over another NHA after Docetaxel and one NHA. For hormone sensitive PCA (mHSPC) multiple meta-analyses have shown combination therapy with Docetaxel or an NHA to be superior to androgen deprivation therapy alone, yet no clear benefit over each other. For peri-interventional chemotherapy with local therapy, there is currently only one positive prospective trial, for very high-risk disease.. Cabazitaxel is underutilized and should be used earlier. NHAs should not be used in succession as there is significant cross resistance. Combination therapy should be used in mHSPC, yet there is no clear benefit for any combination. Peri-interventional chemotherapy might have a benefit for a small group of patients with very high-risk disease, yet this must be carefully evaluated, and side effects must be taken into account.

Topics: Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Metastatic castration-resistant prostate cancer (CRPC) is a potentially symptomatic disease with an eventual lethal outcome. Novel pharmaceutical agents are continuously studied with encouraging results in CRPC.. In this perspective, the authors present established and promising pharmacotherapeutic strategies for the management of CRPC; both with and without metastases. Apart from the different treatment strategies, the authors present the relevant sequence of treatment through disease progression.. Usually, docetaxel should be considered the first line treatment in mCRPC. Abiraterone acetate (AA) plus prednisone or enzalutamide (ENZ) could be alternative treatments in chemotherapy naïve patients. Sipuleucel-T has been approved for the treatment of asymptomatic or minimally symptomatic mCRPC. Ra-223 has been approved for patients with mCRPC with symptomatic bone metastases (not visceral metastases). Cabazitaxel has been approved as the second line treatment to docetaxel in mCRPC. No differences in the overall survival has been observed between sequences starting with docetaxel versus AA/ENZ. Between AA-to-ENZ and ENZ-to-AA sequence, the AA-to-ENZ sequence appeared to be more favorable than the ENZ-to-AA regarding progression-free survival but not overall survival. Carbazitaxel seemed to retain its activity regardless of the treatment sequence. Of note, ENZ and apalutamide have been approved in non-metastatic CRPC.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Immunotherapy; Male; Nitriles; Phenylthiohydantoin; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids; Tissue Extracts

In few years the scenario of metastatic prostate carcinoma treatment has radically changed due to improved knowledge of those mechanisms responsible of prostatic cancer cells survival and proliferation. Five new therapeutic agents (abiraterone acetate, enzalutamide, cabazitaxel, radium-223, sipuleucel-T), all able to improve overall survival, have been introduced in the management of metastatic castration-resistant prostate cancer. Moreover, recent evidences showed that adding docetaxel chemotherapy or abiraterone acetate to androgen deprivation therapy significantly increases overall survival of de novo castration-sensitive metastatic prostate cancer patients. Due to this rapid therapeutic evolution clinicians face one crucial challenge: the choice of the best treatment sequencing. In particular, there are no prospective data to guide clinical decision in patients with progressive disease after docetaxel or abiraterone acetate treatment for castration sensitive disease. In this review we provide an overview of the therapeutic agents available for both castration-sensitive and castration-resistant prostate cancer. We propose some biological and clinical insights helpful in selecting the most appropriate treatment for patients progressing after metastatic castration-sensitive prostate cancer treatment with docetaxel or abiraterone acetate.

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids; Tissue Extracts

Prostate cancer is the most common malignancy in male patients. The second-generation taxanes, cabazitaxel, is a therapeutic option with an overall survival advantage for patients with metastatic castration-resistant prostate cancer. This review explores specific aspects of cabazitaxel including the duration of treatment, the efficacy of lower dose and effect on the incidence of adverse effects, and optimal sequencing of cabazitaxel. A systematic search of data baselines "PubMed, Ovid Medline, Scopus, and Embase" was carried out using the keywords "cabazitaxel" and "metastatic prostate cancer." The search was limited to clinical studies performed after October 2010 addressing duration of treatment, the efficacy of lower dose, adverse effects, the sequence of cabazitaxel in relation to other lines of therapy and use in chemotherapy naïve patients. The current evidence supports the utility and safety of cabazitaxel as either a second- or third-line agent after docetaxel, or as an alternative to docetaxel in the chemotherapy-naive setting. Extended duration of cabazitaxel beyond 10 cycles is feasible and does not appear to lead to cumulative toxicity. In conclusion, cabazitaxel can improve survival in castrate-resistant prostate cancer with an acceptable risk of toxicity. Studies confirmed the efficacy of reduced dose and utility in patients without prior chemotherapy.

Topics: Antineoplastic Agents; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Treatment options for metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years and include cytotoxic agents (e.g., docetaxel and cabazitaxel), immunotherapy (e.g., sipuleucel-T), oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), and targeted alpha therapy (e.g., radium-223 dichloride (radium-223)). Although treatment guidelines have been updated to reflect the availability of new agents, it is not easy to apply them in daily clinical practice because recommendations vary depending on patient comorbidities and disease characteristics. Furthermore, therapeutic accessibility, clinical judgment, and experience affect the selection of treatment options.. In this review, we provide practical guidance for the integration of radium-223 into the management of patients with mCRPC based on our collective clinical experience, as well as the available clinical trial data.. Radium-223 is a targeted alpha therapy; as a bone-seeking calcium mimetic, it accumulates in hydroxyapatite areas surrounding tumor lesions and selectively binds to the areas of increased bone turnover. Radium-223 prolongs overall survival and delays time to the first symptomatic skeletal events in men with mCRPC, and is indicated for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastases. We review its clinical efficacy and safety, practical guidance on identifying the appropriate patient, and recommendations for how best to educate and inform prospective patients regarding their treatment decision making. In addition, we review recent evidence for sequential and combination therapies with radium-223, provide our experiences with these treatment approaches, and discuss their implications for the future treatment of patients with mCRPC.. Based on our clinical experience, radium-223 should be considered relatively early in the treatment course in patients with mCRPC with bone metastases. Coordination of care among multidisciplinary team members, patients, and caregivers is essential for optimizing safe and effective treatment with all CRPC therapies.

Topics: Androstenes; Benzamides; Bone Neoplasms; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Receptors, Androgen; Taxoids; Treatment Outcome

Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab.

Topics: Abiraterone Acetate; Benzamides; Bone Density Conservation Agents; Bone Neoplasms; Clinical Trials, Phase III as Topic; Denosumab; Diphosphonates; Humans; Imidazoles; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Randomized Controlled Trials as Topic; Taxoids; Zoledronic Acid

The aim of this study was to compare the efficacy and safety of docetaxel, cabazitaxel, docetaxel + estramustine, mitoxantrone in the management of castration-resistant prostate cancer (CRPC).. Electronic databases including PubMed, Cochrance Library and Embase were searched for studies published from when the databases were established to January 1st, 2018. Randomized controlled trials (RCTs) that compared docetaxel + prednisone (DP), cabazitaxel + prednisone (CP), docetaxel + estramustine + prednisone (DEP), and mitoxantrone + cabazitaxel + prednisone (MP) for CRPC treatment were identified. The network meta-analysis was conducted with software R 3.3.2. We analyzed the main outcomes, including the overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) response, tumor response and severe adverse events (AEs). Ranking of the chemotherapeutic agents was based on probabilities of interventions for each of the outcomes that were performed. The consistency of direct and indirect evidence was assessed by node splitting.. 10 RCTs, with 3590 patients, were analyzed. The network meta-analysis results revealed that CP significantly increased OS, PFS, PSA response, tumor response, and severe AEs compared to MP. DP showed similar results with CP except for tumor response, where it showed slight inferiority in effectiveness. DEP was associated with clearly improved outcomes in PFS, PSA response and tumor response compared to those of MP, but this was not the case for OS benefit and severe AEs. No significant difference was detected in DP, CP and DEP except for the outcomes of severe AEs. MP was less effective in survival and clinical benefit, but much safer in safety outcomes than other chemotherapy agents. The probabilities of rank plots showed that CP ranked first in OS and tumor response; DEP ranked first in PFS time and PSA response; MP was the best treatment mode for safety.. DP and CP survival benefit (OS, PFS) and clinical benefit (PSA response and tumor response) were comparable, as well as their associated AEs. DEP was associated with less survival benefit, similar clinical improvement and more AEs than DP or CP. MP had the lowest survival and clinical benefit but excellent safety than other agents. Based on evidences of current results, we recommended CP as the most suitable chemotherapy agent for CRPC patients, followed by DP, MP as third, and DEP as the last choice. However, considering limitations of our network meta-analysis, additional high-quality studies are needed for further evaluation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Estramustine; Humans; Male; Middle Aged; Mitoxantrone; Network Meta-Analysis; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Genetic instability is one part of the oncogenic process. Gene mutations involved in DNA repair mechanisms can promote this genetic instability and participate in oncogenesis and metastatic progression. In prostate cancer, DNA repair abnormalities mainly correspond to somatic or constitutional mutations of the BRCA2 and ATM genes. Therapeutic management of metastatic castration-resistant prostate cancer (mCRPC) is currently based on new hormonal therapies (abiraterone, enzalutamide) and taxane-type chemotherapy (docetaxel or cabazitaxel). Preliminary data tend to indicate a specific activity of agents causing DNA breaks (platinum salts) and PARP inhibitors in patients with these DNA repair abnormalities. The frequency of DNA repair gene mutations in patients with prostate cancer (around 20%) and the antitumor response of PARP inhibitors make it a possible short-term therapeutic strategy with several registering clinical trials ongoing.

Topics: Androstenes; Antineoplastic Agents; Benzamides; DNA Damage; DNA Repair; Docetaxel; Genomic Instability; Humans; Male; Nitriles; Phenylthiohydantoin; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

Prostate cancer largely affects aged men and as life expectancy continues to increase, it is likely to be a growing burden requiring an adequate management. Aging is a heterogeneous process, thus, to assess the individual state of health when making decisions is essential. Comprehensive geriatric assessment allows a detailed evaluation of the state of health of a specific subject and can modify the therapeutic decision. It is still not commonly used because it is time consuming. Chemotherapy should be administered equally in aged well-fit patients as in the general population as per the SIOG (International society of geriatric oncology) recommendations for geriatric evaluation and treatment in prostate cancer patients. Chemotherapy with docetaxel or cabazitaxel is expected to have an efficacy and toxicity similar to younger patients and they might be considered treatment options for these patients among others. In vulnerable or frail patients, weekly or biweekly docetaxel regimens are acceptable treatment options.

Topics: Aged; Antineoplastic Agents; Docetaxel; Geriatric Assessment; Humans; Male; Neoplasm Metastasis; Patient Selection; Practice Guidelines as Topic; Prostatic Neoplasms, Castration-Resistant; Taxoids

When advanced prostate cancer recurred during hormonal therapy and became the castration-resistant prostate cancer, "vintage hormonal therapy," such as antiandrogen alternating therapy or estrogen-related hormonal therapy, was widely carried out in Japan until 2013. This vintage hormonal therapy controlled the progression of castration-resistant prostate cancer. When castration-resistant prostate cancer relapses during these therapies, chemotherapy using docetaxel has been carried out subsequently. Since new hormonal therapies using abiraterone acetate and enzalutamide, which improve the prognosis of castration-resistant prostate cancer, became available in Japan from 2014, therapeutic options for castration-resistant prostate cancer have increased. Furthermore, the improvement of the further prognosis is promising by using cabazitaxel for docetaxel-resistant castration-resistant prostate cancer and radium-223 for castration-resistant prostate cancer with bone metastasis. An increase in therapeutic options gives rise to many questions, including best timing to use them and the indication. Furthermore, physicians have to consider the treatment for the recurrence after having carried out chemotherapy. We want to argue the difference in hormonal therapy between Japan and Western countries, and problems when carrying out new treatments, and the importance of imaging in the present review article.

Topics: Abiraterone Acetate; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Disease Progression; Docetaxel; Humans; Japan; Male; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prognosis; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids

Prostate cancer is a highly prevalent form of cancer in older men and is one of the leading causes of death from cancer in men across the globe. Many therapeutic agents have been approved for patients with metastatic castration-resistant prostate cancer (mCRPC), particularly as a post-docetaxel treatment strategy. The objective of this systematic literature review was to assess published efficacy and safety data for select mCRPC therapies - such as abiraterone, cabazitaxel, and enzalutamide - in the post-docetaxel setting.. Database searches of MEDLINE, Embase, and Cochrane CENTRAL, in conjunction with hand searches of multiple congress abstracts, yielded 13 randomized studies and 107 non-randomized studies that met the inclusion criteria.. Randomized studies demonstrated significant improvements in median overall survival (OS) outcomes over placebo for abiraterone (15.8 vs. 11.2 months) and enzalutamide (18.4 vs. 13.6 months), and similar significant improvements were noted for cabazitaxel over mitoxantrone (15.1 vs. 12.7 months). Differences in progression-free survival (PFS) were similarly significant, although variance in the criteria for measuring PFS may limit the extent to which these outcomes can be compared between studies. Non-randomized evidence included multiple publications from several early access and compassionate use programs with a primary objective to report safety outcomes. Results from these studies largely reflected the findings in randomized trials.. Overall, there is a growing body of evidence for post-docetaxel treatment options available in patients with mCRPC. Further head-to-head trials or indirect treatment comparisons may be a valuable method to assess the comparative efficacy of these therapies.

Topics: Androstenes; Benzamides; Compassionate Use Trials; Disease-Free Survival; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Treatments currently available for metastatic castration-resistant prostate cancer (mCRPC) include abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, and radium-223. However, the optimal sequence of these agents is still unclear, and markers to predict treatment response and facilitate patient selection remain an unmet need. In terms of overall survival, it is crucial that patients receive all treatment options currently available. This requires early detection of progression as an indication for a treatment switch. In this context, a structured monitoring of treatment is important in clinical practice.. Für die Behandlung des metastasierten kastrationsresistenten Prostatakarzinoms (mCRPC) stehen aktuell als Therapieoptionen Abirateronacetat, Enzalutamid, Docetaxel, Cabazitaxel und Radium-223 zur Verfügung, wobei die optimale Abfolge in der Therapiesequenz noch unklar ist. Es existieren auch noch keine verlässlichen prädiktiven Biomarker zur Vorhersage des Therapieansprechens und damit zur besseren Patientenselektion. Für das Gesamtüberleben ist entscheidend, dass jeder Patient möglichst alle verfügbaren Therapieoptionen erhält. Dies setzt ein frühzeitiges Erkennen einer Progression als Indikation für einen Therapiewechsel voraus. In diesem Zusammenhang ist die Durchführung eines strukturierten Therapiemonitorings im klinischen Alltag wichtig.

Topics: Abiraterone Acetate; Benzamides; Biomarkers, Tumor; Combined Modality Therapy; Disease Progression; Docetaxel; Humans; Male; Neoplastic Cells, Circulating; Nitriles; Outcome and Process Assessment, Health Care; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids

Despite a growing number of treatment options, metastatic castrate resistant prostate cancer remains almost universally fatal. Dose individualization ensures patients receive the maximal benefit from each line of treatment potentially leading to improved outcomes, a reduction in quality of life impairment and minimization of premature cessation for avoidable toxicity. Herein, we review drug-specific issues that may be associated with unexpected or unrecognized variations in drug systemic exposure despite the use of protocol doses. In particular, we discuss the potential for under-exposure of docetaxel and cabazitaxel; over-exposure of enzalutamide; and varied absorption of abiraterone acetate.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cognition Disorders; Docetaxel; Dose-Response Relationship, Drug; Fatigue; Humans; Male; Precision Medicine; Prostatic Neoplasms, Castration-Resistant; Taxoids

Taxen-based chemotherapy has been established as an effective treatment option in castration-resistant metastatic prostate cancer (mCRPC). Randomized phase III studies, however, have shown that even in the hormone-naïve metastatic state, the early use of chemotherapy in addition to the classical androgen deprivation therapy (ADT) approach leads to a significant increase in median overall survival.. This position paper aims to provide current data and orientation in the evidence-based treatment of mPC patients in daily clinical practice.. A German group of clinical experts analyzed the current data and developed criteria for the treatment of mPC patients in daily clinical practice.. In the current treatment of hormone-naïve mPC, a beneficial effect of chemotherapy in addition to ADT has become evident. Provided patients are in an appropriate condition, those with a high metastatic load should receive chemotherapy in addition to ADT. Especially in high-risk mCRPC patients (PSA >114 ng/ml, visceral metastasis, ADT response <12 months, tumor-associated complaints), first-line chemotherapy is indicated. After docetaxel failure, continuous treatment with cabazitaxel shows superior overall survival compared to sustained antihormonal therapy.. Chemotherapy is firmly established in treating patients with mCRPC. Long-term, it will be important to identify molecular predictors. The authors suggest the early use of chemotherapy in hormone-naïve mPC, but note that the approval in this indication is currently nonexistent. After disease progression, patients should be treated analogous to mCRPC.

Topics: Androgen Antagonists; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Docetaxel; Early Medical Intervention; Evidence-Based Medicine; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Survival Rate; Taxoids

Limited data are available for the use of agents in metastatic castration-resistant prostate cancer (mCRPC) beyond the third-line. We provide data during treatment with cabazitaxel (CAB), helping to improve the informed-consent process.. We retrospectively reviewed patients treated with fourth-line or beyond CAB for mCRPC after failure of previous therapies with docetaxel, abiraterone acetate, enzalutamide and/or radium-223. The progression-free survival (PFS) and the overall survival (OS) were estimated using the Kaplan-Meier method and compared to published data based on a structured literature review. The hospitalization rate was recorded. Factors influencing 6-months OS were analyzed.. Fifteen patients were identified at 4 institutions and included in the analysis. The median PFS was 104 days (range 47-397 days). The median time to death was 10 months (range 2-16). PFS and OS data are in accordance with 17 published patients so far. During the therapy, eleven (73%) of the patients were hospitalized. Prostate-specific antigen (PSA, 500 units; hazards ratio [HR] 1.491, 95% CI 1.000-2.0175), white blood cell count (HR 0.425, 95% CI 0.108-0.952), hemoglobin (HR 0.6014, 95% CI 0.2942-1.0758), and alkaline phosphatase (100 units; HR 1.0964, 95% CI 1.000-1.2859) correlate with 6-months OS.. CAB beyond the third-line is often accompanied by hospitalization. PFS is a significant proportion of the median time of OS. The baseline laboratory might be a good indicator for the decision between CAB and best-supportive care.

Topics: Aged; Antineoplastic Agents; Clinical Decision-Making; Decision Support Techniques; Disease Progression; Disease-Free Survival; Hospitalization; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Palliative Care; Patient Selection; Predictive Value of Tests; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Factors; Taxoids; Time Factors; Treatment Outcome

Since 2010, five new antineoplastic therapies have been FDA approved for the treatment of metastatic prostate cancer. With additional treatment options, questions arose about the optimal sequence of these agents. Until recently, chemotherapy has been deferred until later in the disease course in favor of next-generation androgen deprivation therapy. Prior to the development of abiraterone acetate and enzalutamide, clinical trials were opened investigating the combination of chemotherapy with androgen deprivation therapy in patients with metastatic hormone-sensitive disease. With the development of new oral therapies used to treat castration-resistant disease, these trials were largely forgotten or felt to be obsolete. Recently, two trials have been reported showing an overall survival benefit of the early use of chemotherapy in patients with hormone-naive prostate cancer, changing the treatment paradigm for metastatic disease. Here we review the history of chemotherapy in treating prostate cancer and the emerging evidence favoring its use as first-line therapy against metastatic hormone-sensitive disease.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; History, 20th Century; History, 21st Century; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Time Factors

To present a systematic review of the different therapeutic sequences in metastatic castration-resistant prostate cancer (mCRPC).. Evidence acquisition on therapeutic sequences in mCRPC was performed by a MEDLINE search using combination of the following key words: "prostate cancer," "metastatic," "castration resistant," "enzalutamide," "abiraterone," "treatment sequencing," "cabazitaxel," "docetaxel." A total of 17 studies were included for analysis.. Different sequences have been reported for the treatment of mCRPC: docetaxel after abiraterone, cabazitaxel after docetaxel and abiraterone, abiraterone after cabazitaxel and docetaxel, abiraterone after docetaxel and enzalutamide, and enzalutamide after docetaxel and abiraterone. There are arguments from the preclinical observations suggesting a cross-resistance between docetaxel and abiraterone, and between abiraterone and enzalutamide in mCRPC. Despite limitations, several retrospective clinical reports support these data.. No study of high level of evidence is available to support any recommendation on sequential treatment for mCRPC. There are only clues that prospective clinical studies need to confirm.

Topics: Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Drug Resistance, Neoplasm; Drug Therapy, Combination; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

Prostate cancer is a molecularly heterogeneous disease, and mechanisms of action of taxanes and potential mechanisms of resistance are not clearly defined. Taxanes are microtubule-stabilizing agents resulting in the slowing or blocking of mitosis at the metaphase-anaphase transition and induction of apoptotic cell death. Taxanes also can inhibit androgen receptor pathway. To date, several factors have been associated with taxane resistance, including alterations in tubulin, the effect of drug efflux pumps, and the dysfunctional regulation of signaling pathways that may be involved in resistance to therapy. Preclinical and clinical data support the distinct activity of cabazitaxel in prostate cancer that may overcome resistance to prior taxanes or hormonal therapies. It is challenging to define the most adequate therapeutic sequence for each patient. Moreover, the identification of molecular markers of resistance may help to select patients for specific therapies.

Topics: Clinical Trials as Topic; Humans; Male; Mitosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Taxoids; Treatment Outcome

Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed.

Topics: Androstenes; Anilides; Antineoplastic Agents; Benzamides; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma; Dasatinib; Denosumab; Diphosphonates; Docetaxel; Humans; Imidazoles; Male; Mitoxantrone; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Radioisotopes; Radium; Taxoids; Zoledronic Acid

For men with advanced castration-resistant prostate cancer (CRPC), several treatment options are available, including androgen receptor (AR) pathway inhibitors (abiraterone acetate, enzalutamide), taxanes (docetaxel, cabazitaxel) and the radionuclide (radium-223). However, cross-resistance is a clinically relevant problem. Platinum compounds have been tested in a number of clinical trials in molecularly unselected prostate cancer patients. Advances in CRPC molecular profiling have shown that a significant proportion of patients harbour DNA repair defects, which may serve as predictive markers for sensitivity to platinum agents.. To systematically identify and analyse clinical trials that have evaluated platinum agents in advanced prostate cancer patients.. PubMed was searched to identify published clinical trials of platinum agents in advanced prostate cancer. The PRIMSA statement was followed for the systematic review process. Identified trials are analysed for study design, statistical plan, assessments of anti-tumour activity and the potential value of predictive biomarkers.. A total of 163 references were identified by the literature search and 72 publications that met the selection criteria were included in this review; of these 33 used carboplatin, 27 cisplatin, 6 satraplatin, 4 oxaliplatin and 2 other platinum compounds. Overall, anti-tumour activity varies in the range of 10%-40% for objective response and 20%-70% for PSA decline ≥50%. Response seemed highest for the combinations of carboplatin with taxanes or oxaliplatin with gemcitabine. The interpretation of the clinical data is limited by differences in response criteria used and patient populations studied.. Platinum compounds have moderate anti-tumour activity in molecularly unselected patients with advanced prostate cancer. Translational evidence of DNA repair deficiency should be leveraged in future studies to select prostate cancer patients most likely to benefit from platinum-based therapy.

Topics: Androgen Receptor Antagonists; Benzamides; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Platinum Compounds; Prostatic Neoplasms, Castration-Resistant; Radium; Taxoids; Treatment Outcome

To examine the current literature and identify key consensus findings from the available studies to better educate urologists and medical oncologists on agents used in the treatment of metastatic prostate cancer (mPC).. Following PRISMA guidelines, we conducted a systematic review of the available literature on reported trials of systemic therapies for mPC. Two search terms were used: 'metastatic prostate cancer' and 'treatment'.. A variety of agents have demonstrated improved overall survival in patients with mPC. Twenty recently documented trials were reported in the literature with a focus on enzalutamide, abiraterone acetate, docetaxel and other newer agents. These studies were grouped based on patient populations.. The increasing number of high-quality clinical trials, with overlapping patient populations has made defining the correct therapy for men with mPC challenging for urologists and medical oncologists. The data suggests that the optimal sequence of drugs is not only unknown but also not necessarily the same for each patient. As such, we suggest a more individualized approach to the treatment of prostate cancer depending on patient and disease factors.

Topics: Abiraterone Acetate; Antineoplastic Agents, Hormonal; Docetaxel; Humans; Immunotherapy; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Precision Medicine; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radium; Randomized Controlled Trials as Topic; Taxoids; Tissue Extracts

A growing number of treatment options exist to treat metastatic castrate-resistant prostate cancer (mCRPC), and with these newer options, many questions about optimising treatment remain unanswered. One recommendation that may potentially be overlooked by practitioners is that androgen deprivation therapy (ADT) should be maintained when CRPC develops and when treatment with any of the newer agents is initiated.. However, to emphasise this recommendation, it is valuable to interrogate the evidence for maintaining ADT in different clinical situations.. This statement, reflecting the views of the authors, provides a discussion of this evidence and the rationale behind the recommendation that ADT should be continued in CRPC.

Topics: Androstenes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Practice Guidelines as Topic; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Taxoids; Tissue Extracts

Corticosteroids have been used in the management of prostate cancer for over 30 years. Although daily oral corticosteroids have frequently used in conjunction with chemotherapy for metastatic castration-resistant prostate cancer, their independent impact on survival is unclear. However, corticosteroids confer palliative benefits and are associated with objective responses and circulating tumor cell (CTC) and PSA declines in a small minority of patients, although toxicities such as osteoporosis and immunosuppression complicate long-term use. Following the demonstration of a palliative benefit for mitoxantrone combined with corticosteroids compared with corticosteroids alone, subsequent trials that demonstrated a benefit for first-line docetaxel over mitoxantrone, and second-line cabazitaxel over mitoxantrone, administered concurrent daily oral corticosteroids with all of these agents to maintain uniformity. Conversely, improved outcomes were demonstrated with docetaxel without corticosteroids for metastatic castration-sensitive prostate cancer. Daily oral corticosteroids are routinely combined with abiraterone to mitigate symptoms of mineralocorticoid excess. In contrast daily corticosteroids are not essential when administering enzalutamide or radium-223, and there is a concern of deleterious immune effects concurrently with sipuleucel-T. Given emerging evidence for promotion of resistance mechanisms, routine administration of daily oral corticosteroids in settings other than abiraterone administration and palliation of symptoms is probably not required.

Topics: Adrenal Cortex Hormones; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Mitoxantrone; Palliative Care; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Prostate cancer, and in particular the management options for patients with metastatic castration-resistant prostate cancer (mCRPC), remains an important health issue. The approval of cabazitaxel provides a new treatment option for patients who have progressed despite docetaxel therapy. Clinical use of cabazitaxel in mCRPC is based on the results of the TROPIC study, which demonstrated an approximately 30% reduction in the risk of death compared with mitoxantrone. In this paper, we draw on accumulating clinical experience with cabazitaxel in Australia to discuss important questions such as how to select the right patient for treatment and how to proactively prevent and manage toxicities associated with this therapy. Recognizing the need for a multidisciplinary approach to patient care, opinion and insight has been sought from medical oncologists, nurses and pharmacists. While lack of trial data means that a number of questions remain unanswered, local clinical experience has helped to guide treatment decisions and refine management protocols. Appropriate patient selection, careful ongoing monitoring and proactive management of adverse events will ensure optimal treatment of patients. Nurses in particular play an important role in educating patients and identifying patients at increased risk of developing adverse events with cabazitaxel. The oncology team must work together to educate patients; taking a proactive approach to issues such as adverse events will help maximize the clinical outcome of cabazitaxel treatment and impact positively on the patient's quality of life.

Topics: Australia; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids

Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as “hormone refractory”. In recent years, the concept of hormone refractoriness has been challenged and replaced by “castration resistance”, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.

Topics: Androstenes; Antineoplastic Agents, Hormonal; Benzamides; Biomarkers, Tumor; Disease Progression; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

Despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive prostate cancer progression. Since the approval of docetaxel, four additional agents that show a survival benefit have been registered on the basis of randomized phase 3 trials. These have included enzalutamide and abiraterone, two agents designed specifically to affect the androgen axis, sipuleucel-T, which stimulates the immune system and cabazitaxel, a chemotherapeutic agent. Denosumab was shown to significantly delay skeletal-related events. Clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision making more complex. The induction of constitutively-active AR splice variants (AR-Vs) driving clonal proliferation of AR-negative and AR-independent metastases may be one major potential mechanism of resistance to new hormone therapies.

Topics: Abiraterone Acetate; Androstenes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Bone Neoplasms; Clinical Trials, Phase III as Topic; Denosumab; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Tissue Extracts

New agents for metastatic castration-resistant prostate cancer (CRPC) developed in the past 3 years include cabaziataxel (Cbz), abiraterone acetate (AA) and enzalutamide (E). In this review, the results of clinical studies in which one of these drugs is included as the third line of treatment are discussed. Our review suggests that AA and E have limited activity, while Cbz seems to retain its efficacy. Prospective studies that further examine sequential treatments are warranted.

Topics: Abiraterone Acetate; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

Until 2010, docetaxel was the only agent with proven survival benefit for castration-resistant prostate cancer. The development of cabazitaxel, abiraterone acetate, enzalutamide, radium-223, and sipuleucel-T has increased the number of treatment options. Because these agents were developed concurrently within a short period of time, prospective data on their sequential use efficacy are scarce. The challenge now is to reach a consensus on the best way to sequence effective treatments, ideally by the use of an approach specific to patient subgroups. However, the absence of robust surrogates of survival and the lack of predictive biomarkers makes data for the sequential use of these agents difficult to obtain and interpret.

Topics: Abiraterone Acetate; Androstenes; Benzamides; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Taxoids; Tissue Extracts; Treatment Outcome

Abiraterone acetate is a novel irreversible inhibitor of CYP17 that was recently approved for men with post-chemotherapy or chemo-naive castration-resistant prostate cancer. Unfortunately, this agent is not curative, and patients often ultimately develop resistance. However, men who progress after treatment with this new hormonal agent may be considered for another line of chemotherapy-based treatment. In 2004, docetaxel (D) and prednisone were found to improve survival compared with older regimens. More recently, cabazitaxel (C), a novel taxane chemotherapy, has been found to prolong survival in patients who exhibit disease progression during or after D chemotherapy. Here, we review the first clinical studies in which castration-resistant prostate cancer patients received chemotherapy with D or C after progression during abiraterone acetate treatment.

Topics: Abiraterone Acetate; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytochrome P-450 Enzyme Inhibitors; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Taxoids; Young Adult

Prostate cancer is a tumor addicted to androgen receptor (AR) signaling, even in its castration resistant state, and recently developed antiandrogen therapies including Abiraterone acetate and enzalutamide effectively target the androgen signaling axis, but there is ultimately recurrence to lethal disease. Development of advanced castration-resistant prostate cancer (CRPC) is a biological consequence of lack of an apoptotic response of prostate tumor cells to androgen ablation. Taxanes represent the major clinically relevant chemotherapy for the treatment of patients with metastatic CRPC; unfortunately, they do not deliver a cure but an extension of overall survival. First-generation taxane chemotherapies, Docetaxel (Taxotere), effectively target the cytoskeleton by stabilizing the interaction of β-tubulin subunits of microtubules preventing depolymerization, inducing G2M arrest and apoptosis. Shifting the current paradigm is a growing evidence to indicate that Docetaxel can effectively target the AR signaling axis by blocking its nuclear translocation and transcriptional activity in androgen-sensitive and castration-resistant prostate cancer cells, implicating a new mechanism of cross-resistance between microtubule-targeting chemotherapy and antiandrogen therapies. More recently, Cabazitaxel has emerged as a second-line taxane chemotherapy capable of conferring additional survival benefit to patients with CRPC previously treated with Docetaxel or in combination with antiandrogens. Similar to Docetaxel, Cabazitaxel induces apoptosis and G2M arrest; in contrast to Docetaxel, it sustains AR nuclear accumulation although it reduces the overall AR levels and FOXO1 expression. Cabazitaxel treatment also leads to downregulation of the microtubule-depolymerizing mitotic kinesins, MCAK, and HSET, preventing their ability to depolymerize microtubules and thus enhancing sensitivity to taxane treatment. The molecular mechanisms underlying taxane resistance involve mutational alterations in the tubulin subunits, microtubule dynamics, phenotyping programming of the epithelial-to-mesenchymal transition landscape, and the status of AR activity. This chapter discusses the mechanisms driving the therapeutic resistance of taxanes and antiandrogen therapies in CRPC, and the role of AR in potential interventions toward overcoming such resistance in patients with advanced metastatic disease.

Topics: Androgen Antagonists; Animals; Cell Cycle Checkpoints; Docetaxel; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Humans; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Taxoids

We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC) that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel).. We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS) and severe adverse effects (grade 3 or higher).. Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebo-treated), the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001), 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001) and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001). Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001). Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects linked to elevated mineralocorticoid secretion, compared to placebo (risk ratio for hypokalemia: 5.75, 95% CI 2.08 to 15.90; P = 0.0008; risk-ratio for hypertension: 2.29, 95% CI 1.02 to 5.17; P = 0.05).. In docetaxel-pretreated patients enzalutamide, abiraterone-prednisone and cabazitaxel-prednisone can improve overall survival of patients, compared to placebo or to best of care at the time of study (mitoxantrone-prednisone). Agents targeting the androgen axis (enzalutamide, abiraterone, orteronel) significantly prolonged rPFS, compared to placebo. Further investigation is warranted to evaluate the benefit of combination or sequential administration of these agents. Large-scale studies are also necessary to evaluate the impact of relevant toxic effects observed in a limited number of patients (e.g., enzalutamide-induced seizures, orteronel-induced pancreatitis, and others).

Topics: Abiraterone Acetate; Androstenes; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Evidence-Based Medicine; Humans; Imidazoles; Ipilimumab; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Risk Factors; Survival Analysis; Taxoids; Time Factors; Treatment Outcome

The availability of newly approved treatment options for metastatic castration resistant prostate cancer is not matched with conclusive data on optimal sequencing strategies and resistance patterns. A comprehensive review of efficacy and safety data for new agents and current knowledge regarding treatment sequencing would enable treating physicians to make rational drug selections in patients with metastatic castration resistant prostate cancer.. We searched MEDLINE® and relevant congresses for data on cabazitaxel, docetaxel, 223radium dichloride, abiraterone, enzalutamide and sipuleucel-T, focusing on sequencing strategies, resistance mechanisms and biomarkers of response.. Abiraterone and enzalutamide target the androgen axis with different mechanisms of action. Abiraterone blocks cytochrome P450 17, inhibiting androgen synthesis, whereas enzalutamide inhibits androgen receptor, reducing nuclear translocation of the androgen receptor complex and subsequent DNA binding. Both agents provide improved overall survival in patients with metastatic castration resistant prostate cancer who received prior docetaxel treatment and in those who are chemotherapy naïve. Cabazitaxel provides improved overall survival in patients with metastatic castration resistant prostate cancer with prior docetaxel therapy. Sipuleucel-T provides improved overall survival in asymptomatic patients and (223)radium provides improved overall survival in chemotherapy naïve and chemotherapy treated patients with symptomatic bone metastases. Selecting the correct treatment with metastatic castration resistant prostate cancer is complex as no head-to-head trials have been done and comparison between existing trials is difficult due to differences in study populations and a lack of validated biomarkers. Factors to consider include prior therapy, symptom burden, metastasis type, performance status, comorbidities, adverse event profiles and patient preference. Another consideration is treatment sequence since some agents affect responses to subsequent choices. For example, resistance to abiraterone or enzalutamide may result in limited responses to subsequent androgen targeted agents. Identifying factors predictive of resistance is an area of ongoing research with androgen receptor variants representing a good candidate. Prognostic factors for survival are also likely to be useful and are currently being studied.. New therapies for metastatic castration resistant prostate cancer have brought new challenges with regard to treatment selection and sequencing. While hormonal agents provide good therapeutic responses, resistance may be intrinsic without prior drug exposure. Identifying predictors of response and relevant biomarkers will allow therapies to be more precisely tailored to individual patient profiles.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Agents; Benzamides; Disease Progression; Docetaxel; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Survival Rate; Taxoids; Tissue Extracts

Two new hormonal agents (NHAs), abiraterone and enzalutamide, and one chemotherapeutic agent, cabazitaxel (CABA) improved overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress after docetaxel. Although several analyses of patient cohorts receiving a sequence of two different new agents (NAs) after docetaxel have been published, no definite conclusions can be drawn regarding the best treatment strategy.. All published studies reporting monthly OS rates of mCRPC patients receiving third-line NA after having previously received docetaxel and another NA have been analyzed. The treatments were merged into three groups: one NHA followed by another, one NHA followed by CABA, and CABA followed by one NHA. The cumulative monthly OS rates in each group were determined using a weighted-average approach.. Thirteen retrospective studies including 1016 patients who received NHA/NHA (469), NHA/CABA (318) or CABA/NHA (229) were evaluated. The 12-month OS rates were 28.5%, 61.3%, and 76.4%, respectively. There were no statistically significant differences in terms of known prognostic factors.. Although the retrospective nature of the studies and potential selection biases, our data seem to confirm the potential cumulative survival benefit of using the NAs sequentially after docetaxel. There was no clear superiority of any one of the three strategies, but a sequence that includes CABA seems to suggest a possible OS advantage.

Topics: Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids

Docetaxel is the standard first-line chemotherapy for men with metastatic castration-resistant prostate cancer. Until recently, there was no standard therapy after failure of docetaxel treatment. Cabazitaxel has been shown to improve overall survival in this setting. As a result, the treatment paradigm for mCRPC is changing rapidly. The improved survival shown with cabazitaxel provides an important new opportunity to treat men with mCRPC after docetaxel treatment. Despite the toxicity recorded in the pivotal study, subsequent trials have shown that cabazitaxel is a safe drug. Patient selection and the optimal interval between prior docetaxel treatment and cabazitaxel remain the critical issues. According to a subanalysis of the various studies discussed in this review, there is a patient profile that will probably benefit from use of cabazitaxel after docetaxel failure. Cabazitaxel represents a new treatment option for patients with prostate cancer.

Topics: Antineoplastic Agents; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids

Androgen deprivation is the therapy of choice in the majority of patients with metastatic prostate cancer. However, a state of castration resistance ultimately occurs after hormone therapy, thus defining metastatic castration-resistant prostate cancer (mCRPC). mCRPC has historically been considered a relatively chemoresistant tumor. However, due to its ability to improve survival and the quality of life in comparison with mitoxantrone, docetaxel has been established as the standard chemotherapeutic agent for first-line therapy since 2004. Moreover, recent results have shown that the novel taxane cabazitaxel is able to prolong the overall survival of patients with mCRPC previously treated with docetaxel. Even though these taxanes display a favorable toxicity profile, their routine use in clinical practice requires knowledge about the most frequent and distinct adverse events that may result from their administration.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Docetaxel; Humans; Male; Neutropenia; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.

Topics: Abiraterone Acetate; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radium; Randomized Controlled Trials as Topic; Taxoids; Tissue Extracts

Chemotherapy, once thought to be toxic and ineffective in men with castration resistant prostate cancer (CRPC), has a significant impact on survival and quality-of-life in these patients. This article summarizes recent studies performed with two Food and Drug Administration (FDA) approved agents which have improved survival in men with CRPC, docetaxel and cabazitaxel.. The literature on cytotoxic chemotherapy for castration resistant prostate cancer was reviewed. The individual efficacy, mechanisms of chemotherapeutic action, and appropriate disease states of administration were identified. Recent clinical trial results of chemotherapy combined with targeted agents was also reviewed.. Front line cytotoxic therapy consists of docetaxel combined with prednisone. In two randomized trials, docetaxel based therapy demonstrated a 20%-24% improvement in survival over the palliative standard of care, mitoxantrone combined with prednisone. Eight randomized trials combining docetaxel/prednisone with other antiangiogenic, bone targeted, vaccine or metabolic therapies failed to demonstrate an improvement in survival over docetaxel alone. Cabazitaxel, an analogue of docetaxel which has activity in taxane resistant cell lines, is approved by the FDA, for use in CRPC patients who have previous exposure to docetaxel.. Docetaxel combined with prednisone remains the standard of care as first line cytotoxic therapy for CRPC. Cabazitaxel is an effective second line cytotoxic agent that improves survival; studies are underway comparing cabazitaxel to docetaxel as first line chemotherapy. Given its lack of survival benefit, as well as the emergence of new treatments for prostate cancer, mitoxantrone has a diminished role in the treatment of CRPC.

Topics: Antineoplastic Agents; Docetaxel; Drug Therapy; Drug Therapy, Combination; Humans; Male; Practice Guidelines as Topic; Prednisone; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids; Treatment Outcome

This position paper is intended to help to structure and to standardize therapy monitoring in patients with metastatic castration-resistant prostate cancer (mCRPC). With the treatment options available today, patients with metastatic disease can often maintain good quality of life and stable disease for several years. It is crucial that once a therapy becomes insufficiently effective that it be replaced in a timely manner by a new treatment option. From a prognostic point of view, it is important that patients receive as many as possible and in the ideal case all currently available treatment options.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Benzamides; Disease Progression; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Taxoids

To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC).. The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature.. When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib.. Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients.

Topics: Abiraterone Acetate; Androstadienes; Benzamides; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Practice Guidelines as Topic; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Randomized Controlled Trials as Topic; Taxoids

Enzalutamide, abiraterone-acetate, and cabazitaxel are licensed post-docetaxel treatments of metastatic castration-resistant prostate cancer (mCRPC) in Hungary. The objectives of the study were to assess the efficacy and safety of post-docetaxel enzalutamide treatment and to compare it with abiraterone and with cabazitaxel, using Medline-based systematic literature search, and meta-analysis of randomised controlled trials (RCT). Overall 3 RCTs were included, one for each substance. Compared to placebo, enzalutamide proved significant efficacy in each primary and secondary endpoint. Enzalutamide extended median overall survival by 4.8 months. Due to lack of a common comparator in the cabazitaxel trial, only enzalutamide and abiraterone were involved in an indirect comparison. No significant difference was identified either in the primary endpoint (overall survival) (HR: 0.97, 95% CI: 0.75-1.25) or in frequencies of adverse events between these two treatments. However, enzalutamide was significantly more efficacious than abiraterone in 3 secondary endpoints: time to prostate-specific antigen (PSA) progression (HR: 0.43, 95% CI: 0.31-0.59), radiographic progression-free survival (HR: 0.6, 95% CI: 0.5-0.72), and PSA response rate (RR: 7.48, 95% CI: 2.83-19.72). Enzalutamide therapy proved clinical efficacy and safety in patients with post-docetaxel mCRPC. In the indirect comparison, efficacy and safety of abiraterone and enzalutamide were found to be similar.. Magyarországon jelenleg a metasztatikus, kasztrációrezisztens prosztatarák (mCRPC) terápiájában poszt-docetaxel alkalmazásban enzalutamid, abirateron és cabazitaxel hatóanyagok rendelhetõek. Célunk a Magyarországon 2013-ban törzskönyvezett enzalutamid klinikai hatásosságának és biztonságosságának elemzése és összehasonlítása abirateronnal és cabazitaxellel, szisztematikus irodalomkeresés és randomizált, kontrollált vizsgálatok (RCT) metaanalízissel végzett direkt és indirekt összehasonlítása módszerével. Mindhárom hatóanyag esetében 1-1 RCT került beválogatásra. A három hatóanyag minden elsõdleges és másodlagos végpontban szignifikánsan hatásosabbnak bizonyult a placebónál. Az enzalutamidkezelés a betegek medián túlélését 4,8 hónappal hosszabbította meg. Az indirekt összehasonlításba csak az enzalutamidot és az abirateront vontuk be, a cabazitaxel esetében nem volt közös komparátor. A két terápia között nem találtunk szignifikáns eltérést sem az elsõdleges végpontban (túlélés) (HR: 0,97, 95% KI: 0,75–1,25), sem a nemkívánatos események tekintetében. Három másodlagos végpontban az enzalutamid szignifikánsan hatásosabb az abirateronnál: prosztataspecifikus antigén (PSA) progresszióig eltelt idõ (HR: 0,43, 95% KI: 0,31–0,59), radiológiai progressziótól mentes túlélés (HR: 0,6, 95% KI: 0,5–0,72) és PSA-választ adók aránya (RR: 7,48, 95% KI: 2,83–19,72). Az enzalutamid klinikailag kedvezõ hatású és alkalmazása biztonságos poszt-docetaxel mCRPC kezelésében. Az indirekt összehasonlítás alapján az enzalutamid- és az abirateronkezelés klinikai hatásossága és biztonságossága hasonló.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Benzamides; Bone Neoplasms; Humans; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Despite increasing early detection and treatment of prostate cancer, a subset of patients presents with or develops metastatic disease. Androgen deprivation therapy is effective but resistance eventually develops, resulting in a lethal phenotype known as castration-resistant prostate cancer (CRPC). Recently, several novel treatments, each with distinct mechanisms of actions, have been approved for the treatment of CRPC. Understanding of the metabolic and toxicological considerations of each treatment is crucial to the successful management of patients with this lethal disease.. The present review focuses on the metabolism and toxicology characteristics of recently approved therapies in the treatment of metastatic CRPC. Specifically, the authors review the mechanism of action of these therapies in addition to their, efficacy and usage recommendations for hepatic and renal impairment. The authors, furthermore, also consider their adverse effect profile.. Despite the expanding armamentarium of effective treatments for CRPC, the exact choice, timing and sequence of various therapies remains an inexact science and requires further investigation. Variations in patient comorbidities, disease burden, organ functions and adverse events are all critical determinants in selection of treatment. Identification and validation of molecular pathways and specific targets that drives disease progression will be critical in the continued development of effective treatments in advanced prostate cancer.

Topics: Androgen Antagonists; Antineoplastic Agents; Disease Progression; Drug Approval; Drug Resistance, Neoplasm; Humans; Immunotherapy; Male; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Since 2004, docetaxel-based chemotherapy has been the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), but recently randomised controlled trials (RCTs) of novel agents have shown promise in extending overall survival. These trials have evaluated agents delivered before chemotherapy, to replace or supplement docetaxel, or addressed treatment options for men who have progressed on docetaxel therapy. This review was undertaken to determine which systemic therapies improve cancer- or patient-related outcomes in men with mCRPC.. Searches were carried out in MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. Eligible articles included RCTs comparing systemic therapy or combination (excluding primary or secondary androgen deprivation therapy, bone protective agents or radionuclides) with placebo or other agents in men with mCRPC.. Twenty-five RCTs met the selection criteria. In chemotherapy-naive patients, targeted therapy with tasquinimod conferred a benefit in progression-free survival. Immunotherapy with sipuleucel-T extended overall survival and was well tolerated, but had no effect on the time to disease progression. Hypercastration with abiraterone extended progression-free survival, whereas overall survival was improved but not statistically proven. In the chemotherapy setting, updated and new trials of docetaxel alone confirmed the survival benefit seen in previous studies. A survival benefit with the addition of estramustine to docetaxel shown in a previous study did not lead to an improvement in pain palliation or quality of life. Trials of combining targeted therapies with docetaxel generally did not extend survival. The addition of bevacizumab improved progression-free survival, but not overall survival. The addition of GVAX immunotherapy or calcitriol was harmful. In the post-chemotherapy setting, progression-free and overall survival benefits were detected with cabazitaxel, abiraterone and enzalutamide. Cabazitaxel was associated with greater toxicity, whereas abiraterone and enzalutamide had less severe adverse effects. Satraplatin and sunitinib both extended progression-free survival, but did not improve overall survival.. Docetaxel-based chemotherapy remains the standard of care in men with mCRPC who are candidates for palliative systemic therapy. Promising results are emerging with sipuleucel-T and abiraterone in the pre-docetaxel setting and cabazitaxel, abiraterone and enzalutamide in patients who progress on or after docetaxel. Further research to determine the optimal choice, sequence or even the combination of these agents is necessary.

Topics: Androstenes; Androstenols; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Taxoids; Tissue Extracts

The arrival of several new agents--cabazitaxel, abiraterone acetate, enzalutamide, and radium-223--is changing the treatment options and management of patients with metastatic castration-resistant prostate cancer (mCRPC). Many other novel agents are also being investigated. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. This review article is a summary of a European Treatment Practices Meeting, which was convened to discuss these latest data on novel agents and current treatment strategies in the mCRPC setting.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

The treatment landscape in metastatic castration-resistant prostate cancer (mCRPC) has significantly changed in the recent years. We provide an updated summary of the new therapeutic agents in this disease and discuss open questions and future challenges.. mCRPC is now known to frequently retain sensitivity to hormonal manipulation even after the development of castration resistance, and both the androgen synthesis inhibitor abiraterone and the androgen-receptor antagonist enzalutamide have recently shown to prolong survival in mCRPC patients after chemotherapy. Cabazitaxel, a new-generation antitubulin chemotherapeutic, and the radionuclide radium-223 chloride have also been shown to prolong survival. The biological agent cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against Met and vascular endothelial growth factor receptor 2, demonstrated promising results in a phase II trial and is currently being assessed in two large randomized phase 3 controlled trials.. This recent progress is unprecedented and has already translated to a significant increase in the available armamentarium of drugs for mCRPC. Nonetheless, there are still significant unresolved questions as to the proper sequencing of these novel drugs along the disease continuum. Moreover, the problem of drug resistance, either primary of acquired, continues to be a major therapeutic obstacle.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Anilides; Antineoplastic Agents; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Quality of Life; Radioisotopes; Radium; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Taxoids

As recently as 2004, treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) were limited, with docetaxel the only approved agent conferring a survival benefit. The therapeutic landscape is now very different, with several agents demonstrating prolonged survival since 2010. New agents for the treatment of mCRPC include sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide and radium-223. All are now approved for use in this patient group, although the specific licensing terms vary between agents. In addition, denosumab may have utility in patients with bone metastases. A number of novel agents are also in development with promising initial results. However, because these treatment options have proliferated rapidly, there is currently a paucity of clinical evidence regarding their optimal sequencing. Selection of an appropriate treatment option should take into consideration disease characteristics, drug availability and patient choice. In summary, we discuss several new treatment options available for mCRPC and their integration into the current treatment paradigm.

Topics: Aged; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Quality Improvement; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome; United Kingdom

Prostate cancer is the most commonly occurring solid tumour in men and the second highest cause of cancer deaths. For early stage disease surgery and/or radiation is often curative, and for locally advanced or metastatic disease initial treatment involves removing the drive to tumour growth provided by androgens, via androgen deprivation therapy. In the majority, this treatment eventually fails and castration-resistant prostate cancer (CRPC) develops - a condition with usually a poor prognosis and significant impact on quality of life. For many years mitoxantrone was the only chemotherapy for CRPC, but it had only a palliative effect with no effect on survival. This was followed by docetaxel - the first agent to show an increase in overall survival in metastatic CRPC. Recently, newer agents with different modes of action have been developed. These include the novel taxane, cabazitaxel (which has shown superiority to docetaxel), abiraterone (an anti-androgen), alpharadin (a radionucleotide), sipuleucel-T (a cellular immunotherapy product) and enzalutamide (an androgen receptor blocker), all of which are superior to placebo. This article reviews CRPC and the results of studies with these agents.

Topics: Alpha Particles; Androstenes; Androstenols; Antineoplastic Agents; Benzamides; Cancer Vaccines; Chlorides; Docetaxel; Humans; Male; Mitoxantrone; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Radioisotopes; Radium; Taxoids; Tissue Extracts

The CARD study demonstrated superiority of cabazitaxel over abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who received prior docetaxel and progressed ≤12 months on the alternative androgen-receptor-targeted agent (ARTA). The objective was to compare characteristics and treatment patterns of patients from a real-world dataset with the CARD population.. A large proportion of patients received ≥2 lines of ARTA (35.1%) with 42% of patients who received a first-line ARTA receiving another ARTA in second line. Of the total patients, 452 were eligible for the CARD-like cohort. Median age of the CARD-like cohort was comparable to CARD (73 vs 70 years). The CARD-like cohort had unfavorable disease characteristics vs CARD: ECOG PS ≥ 2 (45% vs 4.7%); metastasis at diagnosis (46% vs 38%) and Gleason 8-10 (65% vs 57%). More patients in the CARD-like cohort received ARTA before docetaxel (48% vs 39%) and received the first ARTA for >12 months (30% vs 17%) compared with CARD. Despite more patients in the CARD-like cohort receiving the lower 20 mg/m. Sequential use of ARTA was frequent. Results indicate the CARD population is reflective of routine clinical practice and duration of response to cabazitaxel was similar in a real-world population.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).. This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%).. A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001).. Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Topics: Humans; Male; Neutropenia; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thrombocytopenia; Treatment Outcome

This trial of 81 men with mCRPC determined the radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) progression-free survival, overall objective response, and safety of AAP or AAP + C. Equally allocated patients received AAP followed by switching to cabazitaxel upon radiographic progression (arm 1) or upfront with AAP + C (arm 2). Patients were stratified into high-/low-risk groups by the Halabi nomogram. Real-time assessment of. Both treatment arms were well-tolerated. Median rPFS in AAP was 6.4 months (95% CI, 3.8 to 10.6) and median overall survival (OS) 18.3 months (95% CI, 14.4 to 37.6), respectively. Fifty-six percent of patients showed ≥50% decline in PSA. Median rPFS in AAP + C was 14.8 months (95% CI, 10.6 to 16.4), and median OS 24.5 months (95% CI, 20.4 to 35.0). There was a ≥50% decline in PSA in 92.1% of men. Neither. AAP + C was safe with improved rPFS, OS duration, and a higher proportion of PSA declines. This suggests that AAP + C given earlier rather than sequentially may benefit some men. Further work is needed to identify this population.

Topics: Abiraterone Acetate; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Previously, results from the TheraP trial showed that treatment with lutetium-177 [. TheraP was a multicentre, open-label, randomised phase 2 trial that recruited men with metastatic castration-resistant prostate cancer after treatment with docetaxel who were suitable for cabazitaxel from 11 hospitals in Australia. Participants were required to be 18 years old or older; have adequate haematological, renal, and liver function; and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned (1:1) using a centralised system using minimisation with a random component and that stratified patients by disease burden, previous treatment with enzalutamide or abiraterone, and study site. Patients were either given cabazitaxel (20 mg/m. In men with metastatic castration-resistant prostate cancer, PSMA-PET SUVmean was predictive of higher likelihood of favourable response to [. Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organisation, Movember Foundation, It's a Bloke Thing, CAN4CANCER, The Distinguished Gentleman's Ride.

Topics: Adolescent; Adult; Australia; Fluorodeoxyglucose F18; Humans; Male; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting.. This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks).. Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001).. Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prognosis; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

In the CARD study (NCT02485691), cabazitaxel significantly improved median radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel and progressed ≤12 mo on the alternative agent (abiraterone/enzalutamide).. To assess cabazitaxel versus abiraterone/enzalutamide in older (≥70 yr) and younger (<70 yr) patients in CARD.. Patients with mCRPC were randomized 1:1 to cabazitaxel (25 mg/m. Analyses of rPFS (primary endpoint) and safety by age were prespecified; others were post hoc. Treatment groups were compared using stratified log-rank or Cochran-Mantel-Haenszel tests.. Of the 255 patients randomized, 135 were aged ≥70 yr (median 76 yr). Cabazitaxel, compared with abiraterone/enzalutamide, significantly improved median rPFS in older (8.2 vs 4.5 mo; hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.38-0.89; p = 0.012) and younger (7.4 vs 3.2 mo; HR = 0.47; 95% CI = 0.30-0.74; p < 0.001) patients. The median OS of cabazitaxel versus abiraterone/enzalutamide was 13.9 versus 9.4 mo in older patients (HR = 0.66; 95% CI = 0.41-1.06; p = 0.084), and it was 13.6 versus 11.8 mo in younger patients (HR = 0.66; 95% CI = 0.41-1.08; p = 0.093). Progression-free survival, prostate-specific antigen, and tumor and pain responses favored cabazitaxel, regardless of age. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 58% versus 49% of older patients receiving cabazitaxel versus abiraterone/enzalutamide and 48% versus 42% of younger patients. In older patients, cardiac adverse events were more frequent with abiraterone/enzalutamide; asthenia and diarrhea were more frequent with cabazitaxel.. Cabazitaxel improved efficacy outcomes versus abiraterone/enzalutamide in patients with mCRPC after prior docetaxel and abiraterone/enzalutamide, regardless of age. TEAEs were more frequent among older patients. The cabazitaxel safety profile was manageable across age groups.. Clinical trial data showed that cabazitaxel improved survival versus abiraterone/enzalutamide with manageable side effects in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and the alternative agent (abiraterone/enzalutamide), irrespective of age.

Topics: Abiraterone Acetate; Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker.. The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608).. High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

Topics: Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Lymphocytes; Male; Neutrophils; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Taxoids

The novel taxane cabazitaxel has been shown to exert excellent anticancer effects after androgen receptor axis-targeting (ARAT) agents in clinical data, but not in in vitro data. We investigated the clinical outcome of cabazitaxel chemotherapy after docetaxel according to use of ARAT agents.. Prostate specific antigen (PSA) response, progression-free survival, and overall survival were compared between cases with and without prior use of ARAT agents in 74 Japanese patients with metastatic castration-resistant prostate cancer treated with cabazitaxel chemotherapy.. Background characteristics were comparable between patients with and without prior use of ARAT agents. PSA response, progression-free survival, and overall survival in cabazitaxel chemotherapy were comparable between patients with and without prior use of ARAT agents.. No detrimental effects of prior ARAT agents on clinical outcome were observed for cabazitaxel chemotherapy in the post-docetaxel setting, suggesting that cabazitaxel can be expected to remain active even after ARAT agent therapy.

Topics: Aged; Androgen Receptor Antagonists; Docetaxel; Humans; Male; Molecular Targeted Therapy; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

Cabazitaxel, used in patients with metastatic castration-resistant prostate cancer (mCRPC), is associated with adverse events which may require dose reductions or discontinuation of treatment. We investigated the potential association of single-nucleotide polymorphisms (SNPs) in genes encoding drug transporters and drug-metabolizing enzymes with cabazitaxel toxicity, overall survival (OS) and pharmacokinetics (PK).. A total of 128 cabazitaxel-treated mCRPC patients, of whom prospectively collected data on toxicity and OS were available and 24 mCRPC patients with available cabazitaxel PK measurements, were genotyped using genomic DNA obtained from EDTA blood. The SLCO1B1 (388A > G; *1B; rs2306283 and 521 T > C; *5; rs4149056 and haplotype SLCO1B1*15), SLCO1B3 (334 T > G; rs4149117), CYP3A4 (*22; rs35599367), CYP3A5 (*3; rs776746), ABCB1 (3435C > T; rs1045642), and TUBB1 (57 + 87A > C; rs463312) SNPs were tested for their association with clinical and PK parameters by univariate/multivariate logistic regression, log-rank test, or Kruskal-Wallis test.. The SLCO1B1*15 haplotype was significantly associated with a lower incidence of leukopenia and neutropenia (p = 0.020 and p = 0.028, respectively). Patients harboring a homozygous variant for SLCO1B1*1B experienced higher rate ≥ grade 3 (p = 0.042). None of the SNPs were associated with pharmacokinetics or OS.. In this study, SLCO1B1 (SLCO1B1*15 and SLCO1B1*1B) was associated with cabazitaxel-induced adverse events in mCRPC patients. As the associations were opposite to previous studies in other drugs and contradicted an underlying pharmacokinetic rationale, these findings are likely to be false-positive and would ideally be validated with even larger (pharmacokinetic) cohorts.

Topics: Aged; Antineoplastic Agents; Disease-Free Survival; Haplotypes; Humans; Leukopenia; Male; Middle Aged; Neutropenia; Polymorphism, Single Nucleotide; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer.. Twenty men were enrolled in this institutuional review board-approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition.. With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m. This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Administration Schedule; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Quality of Health Care; Radiotherapy, Intensity-Modulated; Safety; Taxoids; Treatment Outcome

In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study.. CARD was a randomised, multicentre, open-label, phase 4 study involving 62 clinical sites across 13 European countries. Patients (aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2) with confirmed metastatic castration-resistant prostate cancer were randomly assigned (1:1) by means of an interactive voice-web response system to receive cabazitaxel (25 mg/m. Between Nov 17, 2015, and Nov 28, 2018, of 303 patients screened, 255 were randomly assigned to cabazitaxel (n=129) or abiraterone or enzalutamide (n=126). Median follow-up was 9·2 months (IQR 5·6-13·1). Pain response was observed in 51 (46%) of 111 patients with cabazitaxel and 21 (19%) of 109 patients with abiraterone or enzalutamide (p<0·0001). Median time to pain progression was not estimable (NE; 95% CI NE-NE) with cabazitaxel and 8·5 months (4·9-NE) with abiraterone or enzalutamide (hazard ratio [HR] 0·55, 95% CI 0·32-0·97; log-rank p=0·035). Median time to symptomatic skeletal events was NE (95% CI 20·0-NE) with cabazitaxel and 16·7 months (10·8-NE) with abiraterone or enzalutamide (HR 0·59, 95% CI 0·35-1·01; log-rank p=0·050). Median time to FACT-P total score deterioration was 14·8 months (95% CI 6·3-NE) with cabazitaxel and 8·9 months (6·3-NE) with abiraterone or enzalutamide (HR 0·72, 95% CI 0·44-1·20; log-rank p=0·21). There was a significant treatment effect seen in changes from baseline in EQ-5D-5L utility index score in favour of cabazitaxel over abiraterone or enzalutamide (p=0·030) but no difference between treatment groups for change from baseline in EQ-5D-5L visual analogue scale (p=0·060).. Since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce quality of life when compared with treatment with a second androgen signalling-targeted inhibitor.. Sanofi.

Topics: Aged; Androgen Antagonists; Androgens; Androstenes; Benzamides; Disease-Free Survival; Humans; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids; Treatment Outcome

Our phase III trial showed that biweekly docetaxel (D) is better tolerated than triweekly D in metastatic castration-resistant prostate cancer (mCRPC). The safety of biweekly cabazitaxel (CBZ) post-docetaxel was studied in mCRPC.. A total of 255 4-week cycles of CBZ were administered. The most common grade 3/4 adverse events were neutropenia (16.7%), pain (13.3%), fatigue (10.0%), anemia (5.0%) and non-neutropenic infection (10.0%). PSA responses occurred in 10 patients (16.7%). Clinical benefit rate was 38.3% and median survival 10 months.. Biweekly CBZ is a well-tolerated treatment resulting in meaningful benefits for heavily pretreated mCRPC patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Docetaxel; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Retreatment; Taxoids; Treatment Outcome

Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC).. mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response.. From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS.. Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes.

Topics: Aged; Antineoplastic Agents; Clinical Trials as Topic; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Neoplasm Metastasis; Netherlands; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Standard of Care; Survival Analysis; Taxoids; Treatment Outcome

The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear.. We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed.. A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed.. Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Taxoids

This multi-institutional study aimed to investigate the efficacy and safety profiles of cabazitaxel after prior docetaxel chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 63 Japanese patients with CRPC who were treated with cabazitaxel from 2014 to 2017. The oncological outcomes and adverse events (AEs) were documented, and prognostic factors for oncological outcomes and predictive factors for AEs were analysed. PSA decline was observed in 68.3% of patients, including 25.4% who achieved a ≥ 50% decline. The median progression-free survival, treatment failure-free survival, and overall survival were 4.3, 4.1, and 9.0 months, respectively. More cycles of prior docetaxel therapy was identified as common favourable prognostic factors for progression-free survival, treatment failure-free survival, and overall survival. Severe neutropenia, febrile neutropenia, and severe non-haematological AEs were observed in 73.0%, 33.3%, and 23.8% of patients, respectively. However, > 10 cycles of docetaxel was not associated with increased incidence of AEs. In conclusion, cabazitaxel chemotherapy was still active in Japanese CRPC patients treated with > 10 cycles of docetaxel chemotherapy, with an acceptable risk of AE burden. Treatment with cabazitaxel after > 10 cycles of docetaxel may be an appropriate option when it can be administered.

Topics: Aged; Antineoplastic Agents; Docetaxel; Drug Administration Schedule; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

The androgen receptor splice variant (AR-V) 7 in circulating tumor cells (CTCs) is a predictor for resistance to anti-AR-targeted treatment, but not to taxane-based chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). In this study, we investigated whether the presence of two constitutively active variants (AR-V3, AR-V7) and two other conditionally activated variants (AR-V1, AR-V9) vs full-length androgen receptor (AR-FL) measured in CTCs from patients with mCRPC were associated with outcome to therapy with the taxane cabazitaxel. Blood was collected at baseline and after two cycles of cabazitaxel from 118 mCRPC patients starting cabazitaxel in a prospective phase II trial. CellSearch-enriched CTCs were enumerated and in parallel characterized for the presence of the AR-Vs by reverse transcription quantitative polymerase chain reaction. Correlations with CTC and prostate-specific antigen response to cabazitaxel as well as associations with overall survival (OS) were investigated. All AR-Vs were frequently present and co-expressed at frequencies of 31-48% at baseline and at 19-40% after two cycles of cabazitaxel. No specific directions of change in the measured variants were detected between the start of treatment and after two cycles of cabazitaxel. No associations between the presence of AR-V3 and AR-V7 and outcome to cabazitaxel were observed. While a reduction in CTCs to < 5 CTCs during treatment (CTC5-response) was less often observed in patients with AR-V9-positive CTCs at baseline (P = 0.004), the CTC5-adjusted detection of AR-V1 after two cycles of cabazitaxel was an independent prognostic factor for OS [HR 2.4 (95% CI 1.1-5.1, P = 0.03)]. These novel findings are expected to contribute to more personalized treatment approaches in mCRPC patients.

Topics: Aged; Alternative Splicing; Cell Count; Humans; Male; Neoplastic Cells, Circulating; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Survival Analysis; Taxoids; Treatment Outcome

Cabazitaxel is an efficacious treatment for patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel, but febrile neutropenia during the first cycle is a frequent complication. Asian patients are at increased risk of febrile neutropenia. Although primary prophylaxis with granulocyte colony-stimulating factor can reduce the incidence, its efficacy has not been prospectively demonstrated in Japanese patients with cabazitaxel treatment.. PEGAZUS, a prospective, single-arm study conducted at eight clinical sites in Japan, enrolled 21 heavily pretreated patients with metastatic castration-resistant prostate cancer. Patients received cabazitaxel 25 mg/m2 every 3 weeks, up to 10 cycles. Oral prednisolone 10 mg was taken daily. Pegfilgrastim 3.6 mg was administered at least 24 h after the cabazitaxel infusion. The primary endpoint was the incidence of febrile neutropenia in the first cycle.. The median number of treatment cycles was seven. The relative dose intensity of cabazitaxel was 67.4% (range, 53.2-91.3%). Two of 21 patients (9.5%) experienced febrile neutropenia in the first cycle. This rate was lower than the rate (43%) previously observed without prophylactic granulocyte colony-stimulating factor in a similar patient population. Six patients showed a prostate-specific antigen response (28.6%). Three of four patients evaluable for tumor response had stable disease and one had progressive disease. Grade ≥3 diarrhea was not observed. Primary prophylaxis with granulocyte colony-stimulating factor significantly reduced the incidence of febrile neutropenia in this study.. Cabazitaxel plus granulocyte colony-stimulating factor is safe and effective for Japanese patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel. Clinical trial registration: ClinicalTrials.gov (NCT02441894).

Topics: Aged; Aged, 80 and over; Filgrastim; Humans; Japan; Male; Middle Aged; Neoplasm Metastasis; Polyethylene Glycols; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

The phase III PROSELICA trial showed that cabazitaxel 20 mg/m (C20) was not inferior and better tolerated compared to cabazitaxel 25 mg/m (C25) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed during or after docetaxel. Here, we report on a real-world retrospective analysis concerning the safety and the activity of C20 schedule in patients with mCRPC treated at our Institution. We identified 35 patients with mCRPC who received C20 as baseline dose treatment because they were frail or experienced serious toxicities to previous treatments. Adverse events assessment was performed at each visit during the treatment. Progression-free survival (PFS) and overall survival (OS) curves were obtained using the Kaplan-Meyer product-limit estimator. Median age was 71 years. All patients received a previous treatment with docetaxel; 19 patients (54%) received one additional line of therapy and 9 (26%) two or more. Patients received a median of 4 cycles (range: 2-10). Only one patient experienced grade 3 neutropenia (3%), two patients grade 3 anemia (6%), and one patient grade 3 fatigue (3%); three patients were treated with prophylactic Granulocyte colony-stimulating factor (9%). The most frequent adverse events of all grades were: anemia (39%), fatigue (33%), and diarrhea (15%). Median PFS was 3.7 months [95% confidence interval (CI): 3.31-4.09]; median OS was 10.3 months (95% CI: 4.63-15.97). Our real-world analysis confirms that C20 is a feasible option for elderly and heavily pretreated patients with mCRPC, showing activity and good tolerability.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids

Cabazitaxel use has usually been limited to up to 10 cycles in most countries according to the protocol in the TROPIC trial. Therefore, clinical data on cabazitaxel use beyond 10 cycles is limited. The aim of this study was to report the therapeutic outcome of cabazitaxel chemotherapy administered for >10 cycles.. This study included 74 Japanese patients with prostate cancer between 2014 and 2017. Patients background, and treatment outcomes including PSA decline, progression-free survival, treatment-failure-free survival, overall survival, and adverse events were investigated, comparing patients treated with ≤10 and >10 cycles.. Patients characteristics were favorable as indicated by the higher number of cycles of prior docetaxel chemotherapy, absence of pain, and absence of bony and visceral metastases among men who received >10 cycles of cabazitaxel. PSA response, progression-free survival, treatment-failure-free survival and overall survival were better among patients treated with >10 cycles of cabazitaxel compared to those treated with ≤10 cycles. The incidence of severe adverse events was similar between the two groups.. Taken together, this study suggested that continuous chemotherapy with cabazitaxel beyond 10 cycles may be beneficial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Humans; Male; Middle Aged; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

To assess the toxicity and effectiveness of contemporary metastatic castrate-resistant prostate cancer (mCRPC) treatments at a population level, among all patients in Ontario particularly treated with newer agents, including abiraterone, enzalutamide, docetaxel, and cabazitaxel.. We performed a population-based, retrospective cohort study of 2439 men aged ≥65 years treated for mCRPC with abiraterone, enzalutamide, docetaxel, or cabazitaxel from 2003 to 2015 in Ontario, Canada. Our primary outcome was treatment-related toxicity, defined as hospitalizations and emergency room (ER) visits during mCRPC treatment. Based on toxicity profiles identified during phase III trials, we further identified specific treatment-related toxicity. We calculated hazard ratios (HRs) using multivariable Cox proportional hazards models with time-varying exposures.. Abiraterone and enzalutamide exposure were not associated with any-cause (P = .19 and .52, respectively) or treatment-related (P = .45 and .64, respectively) toxicities. In contrast, docetaxel exposure was associated with an increased risk of any-cause (HR 1.29, 95% confidence interval [CI] 1.15-1.44) and treatment-related (HR 1.52, 95% CI 1.33-1.74) toxicities. Cabazitaxel exposure was associated with a significant risk of treatment-related toxicity (HR 5.94, 95% CI 1.87-18.92) but not any-cause toxicity (HR 2.37, 95% CI 0.59-9.63).. Among patients with mCRPC, we failed to show any increased risk of hospitalizations and ER visits for treatment-related complications for abiraterone or enzalutamide. In contrast, treatment with intravenous chemotherapeutic agents was associated with an increased risk of hospitalizations and ER visits to manage these complications.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Canada; Cohort Studies; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Emergency Service, Hospital; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Multivariate Analysis; Nitriles; Ontario; Phenylthiohydantoin; Population Surveillance; Prognosis; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome

The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown.. To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences.. Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016.. The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity.. A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3.. In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs.. The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.

Topics: Abiraterone Acetate; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Multivariate Analysis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor-targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

Topics: Aged; Biomarkers, Tumor; Cell Nucleus; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Humans; Kallikreins; Male; Neoplastic Cells, Circulating; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids

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.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

The purpose of this study was to evaluate the efficacy of cabazitaxel for patients with metastatic castration-resistant prostate cancer (mCRPC) after sequential therapy with docetaxel (DTX) and single or dual regimens of novel androgen receptor-axis-targeted (ARAT) agents. We retrospectively reviewed 84 consecutive patients treated with cabazitaxel at Kobe University Hospital and related hospitals from September 2014 to September 2016. The association of each prognostic parameter with progression-free survival (PFS) was evaluated, including the sequence of therapy. Patients were divided according to their treatment after receiving cabazitaxel as follows: group 1 (after DTX and single regimen of novel ARAT agent) and group 2 (after DTX and dual novel ARAT agents). Median PFS for cabazitaxel treatment was 10.3 months (range 4.5-14.2 months). Prostate-specific antigen (PSA) response rates (≥30%) were 46.8 and 46.1% in group 1 and group 2, respectively [p = 0.96, hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.57-1.80]. PSA response rates (≥50%) were 43.8 and 26.9% in patients of group 1 and group 2, respectively (p = 0.18, HR 1.54, 95% CI 0.78-3.04). Univariate analysis revealed that PFS for cabazitaxel treatment was significantly associated with baseline alkaline phosphatase, bone metastasis, and prior sequential therapy. Multivariate analysis revealed that bone metastasis and prior sequential therapy were independently associated with PFS. Prior sequential therapy with single regimen or dual regimens of novel ARAT agents was independently associated with PFS of patients with mCRPC treated with cabazitaxel. The effect of cabazitaxel after the administration of DTX and single novel ARAT agent was more sustained.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Male; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with metastatic castration-resistant prostate cancer. Custirsen (OGX011) is a second generation highly specific antisense oligonucleotide that inhibits the production of clusterin, an antiapoptotic protein that is upregulated in response to chemotherapy and that confers treatment resistance. We aimed to assess whether custirsen in combination with cabazitaxel and prednisone increases overall survival in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.. In this randomised, open-label, international, phase 3 trial, men with radiographically documented metastatic castration-resistant prostate cancer that had progressed after docetaxel treatment with a Karnofsky performance status of more than 70% and who were fit for chemotherapy, were recruited from 95 cancer treatment centres in eight countries. Patients were randomly assigned (1:1) centrally using permuted blocks (block size 8) to receive cabazitaxel plus prednisone (cabazitaxel 25 mg/m. Between Sept 9, 2012, and Sept 29, 2014, 795 patients were screened for enrolment. 635 men were eligible for inclusion and were randomly assigned (n=317 in the cabazitaxel and prednisone plus custirsen group and n=318 in the cabazitaxel and prednisone group). Median follow up was 28·3 months (IQR 24·4-34·5) for the custirsen group and 29·8 months (IQR 25·3-35·2) for the control group. Median overall survival in all randomly assigned patients did not differ between the two groups (14·1 months [95% CI 12·7-15·9] in the curtisen group vs 13·4 months [12·1-14·9] in the control group; hazard ratio [HR] 0·95 [95% CI 0·80-1·12]; log-rank p=0·53). In the poor prognosis subgroup, median overall survival also did not differ between the two treatment groups (11·0 months [95% CI 9·3-13·3] in the custursin group vs 10·9 months [8·2-12·4] in the control group; HR 0·97 [95% CI 0·80-1·21]; two-sided p=0·80). The most frequently reported grade 3 or worse adverse events in the custirsen versus control groups were neutropenia (70 [22%] of 315 vs 61 [20%] of 312), anaemia (68 [22%] vs 49 [16%]), fatigue (23 [7%] vs 18 [6%]), asthenia (16 [5%] vs 8 [3%]), bone pain (16 [5%] vs 5 [2%]), and febrile neutropenia (16 [5%] vs 9 [3%]). Serious adverse events were reported in 155 (49%) versus 132 (42%). 27 patients died within 30 days of treatment in the cabazitaxel and prednisone plus custirsen group, seven of which were deemed to be treatment related, versus 17 in the cabazitaxel and prednisone group, eight of which were deemed to be treatment related. Of the 21 deaths reported, 15 were reported as complications related to study treatment, either chemotherapy (eight and three, respectively) or study drug (none and four, respectively).. We noted no survival benefit in men with metastatic castration-resistant prostate cancer with the addition of custirsen to cabazitaxel and prednisone treatment. Cabazitaxel and prednisone remains the standard of care for patients with metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy.. OncoGenex Pharmaceuticals.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Internationality; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prednisone; Prognosis; Proportional Hazards Models; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids; Thionucleotides; Tomography, X-Ray Computed; Treatment Outcome

Cabazitaxel (CBZ), a novel tubulin-binding taxane, improves overall survival in metastatic castration-resistant prostate cancer (mCRPC) that progresses during or after docetaxel treatment. We have designed a phase II study to evaluate the efficacy and safety of CBZ as a weekly schedule for 'unfit' mCRPC patients after docetaxel failure.. In this single arm phase II study. CBZ was weekly administered in 1-hour infusion on days 1, 8, 15 and 22, every 5 weeks at 10 mg/m. Seventy patients (median age: 73.9 years) were enrolled; overall, 71.4% had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 2; and 84%, 16% and 11% had bone, liver and lung metastases, respectively. Objective partial response or stable disease was achieved in 61% of patients, while PSA responses of ≥50% and ≥80% were observed in 34.8% and 10.6%, respectively. The median PSA-PFS was 4.8 months; and 68.6% of patients had no progression at week 12. The most frequent grade 3/4 toxicities were neutropenia (2.8%), leukopenia (5.7%) and thrombocytopaenia (9%); no cases of febrile neutropenia were reported. Early CTC response was significantly correlated with PSA-PFS.. CBZ/prednisone administered weekly to 'unfit' mCRPC patients appears to be as effective as classical standard 3-week scheme (TROPIC study) but with significantly lower toxicities and better tolerance. Early CTC response appears to be valuable as an early end-point of therapeutic efficacy.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Humans; Kallikreins; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Spain; Taxoids; Time Factors; Treatment Outcome

Tasquinimod is an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer activity in preclinical studies and in clinical trials of men with metastatic castration resistant prostate cancer (mCRPC), including single agent activity and in combination with taxanes. We sought to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of tasquinimod in combination with cabazitaxel and prednisone in men with chemorefractory mCRPC.. Men with mCRPC who had failed prior docetaxel chemotherapy received cabazitaxel 25 mg/m. We enrolled 25 men with chemorefractory mCRPC. The RP2D was 0.5 mg tasquinimod based on excess DLTs (two of three men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation. Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function abnormalities. The proportion of men with a ≥30% PSA decline was 63% and the median composite progression-free survival (PFS) was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with six men receiving >10 cycles. Best overall RECIST responses (CR + PR) were observed in three men (12%), with stable disease in 12 (48%). No pharmacokinetic interactions were observed.. We determined the RP2D of tasquinimod combined with cabazitaxel to be 0.5 mg daily following a 3 week lead-in of tasquinimod 0.25 mg with growth factor support. No unexpected toxicities occurred. Prostate 77: 385-395, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Humans; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Quinolones; Survival Rate; Taxoids; Treatment Outcome

Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536).. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II).. Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors.. The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

In patients with metastatic castration-resistant prostate cancer (mCRPC), bone-seeking radiopharmaceuticals, such as Re-hydroxyethylidene diphosphonate (HEDP), are effective for pain palliation and have a marked antitumor effect. Cabazitaxel is the standard second-line chemotherapy for mCRPC patients. We performed a phase 1 study investigating the safety and feasibility of the combined treatment with Re-HEDP and cabazitaxel in mCRPC patients.. Patients with mCRPC and documented disease progression on or after docetaxel were eligible for inclusion. In both dose levels, cabazitaxel (4 cycles of cabazitaxel 25 mg/m + 2 cycles of cabazitaxel 20 mg/m in level 1, and 6 cycles of cabazitaxel 25 mg/m in level 2) were combined with 2 cycles of Re-HEDP 40 MBq/kg (1.1 mCi/kg) (after the second and fourth cabazitaxel cycles). Three patients were planned for each dose level, expanding to 6 patients in case of a dose-limiting toxicity (DLT). A DLT is defined as any grade 4 toxicity, or grade 3 toxicity delaying the next treatment cycle.. Twelve patients were included, of whom 3 had progressive disease before the third cycle of cabazitaxel. In total, 1 DLT occurred (dose level 1) after treatment cycle 6 (Re-HEDP) (thrombopenia grade 3 delaying the next treatment cycle). The cohort was expanded to 6 patients, with no further DLTs. No DLT occurred in dose level 2. The most important adverse events were of hematologic origin, followed by mild fatigue and diarrhea.. Combination therapy with cabazitaxel and Re-HEDP is feasible and generally well tolerated with similar hematologic toxicity compared with cabazitaxel monotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Docetaxel; Etidronic Acid; Humans; Male; Middle Aged; Neoplasm Metastasis; Organometallic Compounds; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Cabazitaxel significantly improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel, but is associated with a higher rate of grade ≥3 neutropenia compared with docetaxel. We thus examined the relationship between cabazitaxel-induced grade ≥3 neutropenia, baseline neutrophil-lymphocyte ratio (NLR) and treatment outcomes.. Data from the experimental arm of the TROPIC phase 3 trial which randomly assigned men with mCRPC to cabazitaxel or mitoxantrone every 3 weeks, both combined with daily prednisone, were analysed. The influence on OS (primary end-point) and progression-free survival (PFS) of at least one episode of grade ≥3 neutropenia during cabazitaxel therapy was investigated using Cox regression models, adjusted for pain at baseline. The relationships with prostate-specific antigen (PSA) responses during cabazitaxel therapy and baseline NLR were also analysed.. The occurrence of grade ≥3 neutropenia during cabazitaxel therapy was associated with a prolonged OS (median 16.3 versus 14.0 months, hazard ratio (HR) [95% confidence interval] = 0.65 [0.43-0.97], p = 0.035), a twice longer PFS (median 5.3 versus 2.6 months, HR = 0.56 [0.40-0.79], p = 0.001) and a higher confirmed PSA response ≥50% (49.8% versus 24.4%, p = 0.005), as compared with patients who did not develop grade ≥3 neutropenia. Grade ≥3 neutropenia was more common in case of NLR <3 as compared with NLR ≥3 at baseline (88.8% versus 75.3%, p = 0.002). Combining low NLR at baseline and grade ≥3 neutropenia during therapy was associated with the longest OS (median 19.2 months) while high NLR at baseline and no grade ≥3 neutropenia was associated with a poor OS (median 12.9 months, HR 0.46 [0.28-0.76], p = 0.002). In the subgroup of neutropenic patients the median OS was 19.7 months in those treated with granulocyte colony-stimulating factor (G-CSF) and 16 months on those without G-CSF support.. This post-hoc analysis of TROPIC suggests that the occurrence of grade ≥3 neutropenia with cabazitaxel is associated with improved OS and PFS. Patients with a low NLR at baseline were more likely to develop grade ≥3 neutropenia during cabazitaxel therapy and showed the longest OS. High NLR at baseline and no grade ≥3 neutropenia during therapy was associated with poor outcomes which may suggest insufficient drug exposure or a limited impact on the tumour-associated immune response. Primary or secondary prophylactic use of G-CSF had no adverse impact for outcome. If prospectively confirmed, these results would justify maintaining the intended cabazitaxel dose of 25 mg/m(2) whenever possible.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Granulocyte Colony-Stimulating Factor; Humans; Kallikreins; Kaplan-Meier Estimate; Lymphocyte Count; Lymphocytes; Male; Mitoxantrone; Neoplasm Metastasis; Neutropenia; Neutrophils; Prednisone; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Severity of Illness Index; Taxoids; Time Factors; Treatment Outcome

TMPRSS2-ERG rearrangement is a genetic alteration exclusive to prostate cancer, associated with taxane resistance in preclinical models. Its detection in blood samples of metastatic resistant prostate cancer (mCRPC) patients may indicate the presence of circulating tumour cells with this genetic alteration and may predict taxane resistance. To test this hypothesis, we evaluated TMPRSS2-ERG expression using quantitative reverse transcription polymerase chain reaction in peripheral blood mononuclear cells and tumour tissue from mCPRC patients treated with taxanes. We examined peripheral blood mononuclear cells from 24 healthy controls, 50 patients treated with docetaxel, and 22 with cabazitaxel. TMPRSS2-ERG was detected in 0%, 16%, and 22.7% of them, respectively. In docetaxel-treated patients TMPRSS2-ERG detection correlated with lower prostatic-specific antigen (PSA) response rate (12.5% vs 68.3%, p=0.005), PSA-progression-free survival (PFS; 3.1 mo vs 7.5 mo, p<0.001), clinical/radiological-PFS (3.1 mo vs 8.2 mo, p<0.001), and it was independently associated with PSA-PFS (hazard ratio 3.7; p=0.009) and clinical/radiological-PFS (hazard ratio 6.3; p<0.001). Moreover, TMPRSS2-ERG also predicted low PSA-PFS to cabazitaxel. At progression, a switch from negative to positive TMPRSS2-ERG was observed in 41% of patients with undetected TMPRSS2-ERG at the baseline sample. Tissue TMPRSS2-ERG expression correlated with lower PSA-PFS (p=0.02) to docetaxel. Our findings support the potential role of TMPRSS2-ERG detection as a biomarker to tailor treatment strategies.. Taxanes are the most active chemotherapy agents in metastatic resistant prostate cancer. However, not all patients respond to this therapy. In the present study we show that the detection of TMPRSS2-ERG in blood from metastatic resistant prostate cancer patients predicts resistance to docetaxel and it may be useful to select treatment and to avoid possible toxicities in refractory patients.

Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oncogene Proteins, Fusion; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

The neutrophil-lymphocyte ratio (NLR), proposed as an indicator of cancer-related inflammation, has known prognostic value in prostate cancer. We examine its association with survival (OS) and response in patients treated with second-line chemotherapy.. We analysed patients with metastatic castration-resistant prostate cancer (mCRPC) treated in the TROPIC trial, evaluating cabazitaxel versus mitoxantrone. Cox regression models were used to investigate the association of baseline NLR (BLNLR) with OS and the significance of a change in NLR count with treatment. Logistic regression models were used to determine the association of BLNLR counts with prostate specific antigen (PSA) and RECIST responses. The optimal NLR cut-off was established based on the concordance index of different values.. Data from 755, 654 and 405 patients was available for OS, PSA and RECIST response analysis respectively. Median OS was 14.0 months [95% confidence interval (CI) 13.2-14.8]. Median NLR was 2.9 (IQR: 1.9-5.1). BLNLR was associated with survival (HR 1.5, 95% CI 1.1-2.1, P = 0.011) in multivariable analysis (MVA) independently of variables included in the Halabi nomogram, treatment arm and corticosteroid use. The optimal cut-off for a dichotomous NLR was selected at 3.0 based on its higher c-index related to survival. BLNLR ≥3.0 was associated with lower PSA response (40.1% versus 59.9%; P < 0.001) and RECIST response (7.7% versus 15.6%, P = 0.022) in MVA. Conversion from high (≥3) to low (<3) NLR was associated with improved survival (HR 0.66; 95% CI 0.51-0.85; P = 0.001) and higher PSA response rates (66.4% versus 33.6%; P = 0.000). Use of corticosteroids at baseline did not modify the association between NLR and survival.. NLR is a valid prognostic biomarker in CRPC and is associated with survival, PSA and RECIST responses in patients treated with second-line chemotherapy. Changes in NLR counts with treatment may indicate benefit. NLR prognostic value is independent of prior use of corticosteroids.. NCT00417079.

Topics: Adrenal Cortex Hormones; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Follow-Up Studies; Humans; Lymphocytes; Male; Middle Aged; Mitoxantrone; Neoplasm Staging; Neutrophils; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids

To compile the safety profile and quality of life (QoL) data for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel in the UK Early Access Programme (UK EAP).. A total of 112 patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. Patients received cabazitaxel 25 mg/m(2) every 3 weeks with prednisolone 10 mg daily for up to 10 cycles. Safety assessments were performed before each cycle and QoL was recorded at alternate cycles using the EQ-5D-3L questionnaire and visual analogue scale (VAS). The safety profile was compiled after completion of the UK EAP and QoL measures were analysed to record trends. No formal statistical analysis was carried out.. The incidences of neutropenic sepsis (6.3%), grade 3 and 4 diarrhoea (4.5%) and grade 3 and 4 cardiac toxicity (0%) were low. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. There were trends towards improved VAS and EQ-5D-3L pain scores during treatment.. The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important.

Topics: Aged; Antineoplastic Agents; Humans; Male; Middle Aged; Patient Safety; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids; United Kingdom

We previously reported the pharmacokinetic profile and preliminary tolerability of cabazitaxel in a phase I study in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report the final safety profile and anti-tumor activity of cabazitaxel in a larger population, including all patients enrolled in the expansion cohort of the study.. Japanese patients with mCRPC previously treated with docetaxel received cabazitaxel intravenously every 3 weeks plus daily prednisolone. In patients treated with the maximum tolerated dose of 25 mg/m(2) we evaluated adverse events including treatment-related neutropenia, prostate-specific antigen (PSA) response and objective response.. In total, 44 patients were treated with the maximum tolerated dose. The most frequent adverse events (any grade) were neutropenia (100 %), febrile neutropenia (54.5 %), fatigue (54.5 %), nausea (52.3 %) and diarrhea (50.0 %). There were no deaths due to treatment-related adverse events. Neutropenia with prior docetaxel did not appear to influence the probability of febrile neutropenia with cabazitaxel. Most patients received therapeutic granulocyte colony-stimulating factor (G-CSF; cycle 1: 86.4 %; cycle 2 or later: 81.8 %). In the efficacy population, two of 12 patients with measurable disease had partial response (objective response rate: 16.7 %), while 10 had stable disease. PSA response rate was 29.3 % (12/41 patients). Median time to PSA progression was 3.68 months (95 % confidence interval 1.35-4.63).. In this heavily pretreated Japanese population, the occurrence of neutropenia and febrile neutropenia was high, suggesting G-CSF prophylaxis may be required as part of toxicity management. However, the efficacy of cabazitaxel was consistent with global studies. ClinicalTrials.gov identifier: NCT01324583.

Topics: Aged; Antineoplastic Agents; Docetaxel; Dose-Response Relationship, Drug; Humans; Japan; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Taxoids

Docetaxel is a cornerstone treatment for metastatic, castration resistant prostate cancer (CRPC) which remains a leading cause of cancer-related deaths, worldwide. The clinical usage of docetaxel has resulted in modest gains in survival, primarily due to the development of resistance. There are currently no clinical biomarkers available that predict whether a CRPC patient will respond or acquire resistance to this therapy. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting. Importantly, we identified MDR-1, MDR-3, Endophilin-A2 and PABP4 that were enriched only in DU145 Tax-Res exosomes. We validated the presence of these proteins in the serum of a small cohort of patients. DU145 cells that have uptaken DU145 Tax-Res exosomes show properties of increased matrix degradation. In summary, exosomes derived from DU145 Tax-Res cells may be a valuable source of biomarkers for response to therapy.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Biomarkers, Tumor; Blood Proteins; Cell Death; Cell Line, Tumor; Cohort Studies; Computational Biology; Docetaxel; Drug Resistance, Neoplasm; Exosomes; Extracellular Matrix; Humans; Intracellular Signaling Peptides and Proteins; Male; Nanoparticles; Poly(A)-Binding Proteins; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Proteome; Taxoids

Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide. Cabazitaxel might, however, remain effective in AR-V7-positive patients.. To investigate the association between AR-V7 expression in CTCs and resistance to cabazitaxel.. We selected patients with mCRPC from the multicenter, randomized, phase 2, randomized, open-label, multicenter study in mCRPC on the pharmacodynamic effects of budesonide on cabazitaxel (Jevtana) (CABARESC). Before the start of the first and third cabazitaxel cycle, CTCs were enumerated using the CellSearch System. In patients with ≥10 CTCs in 7.5 ml blood at baseline, the expression of AR-V7 was assessed by quantitative polymerase chain reaction.. The primary end point was the association between the AR-V7 status and the CTC response rate (decrease to fewer than five CTCs in 7.5 ml blood during treatment). Secondary end points were the prostate-specific antigen (PSA) response rate (RR) and overall survival (OS). Analyses were performed using chi-square and log-rank tests.. AR-V7 was detected in 16 of 29 patients (55%) with ≥10 CTCs and was more frequently found in abiraterone pretreated patients (5 of 5 [100%] treated vs 7 of 20 [35%] untreated; p=0.009). We found no differences in CTC and PSA RRs. The presence of AR-V7 in CTCs was not associated with progression-free survival (hazard ratio [HR]: 0.8; 95% confidence interval [CI], 0.4-1.8) or overall survival (HR 1.6; 95% CI, 0.6-4.4).. The response to cabazitaxel seems to be independent of the AR-V7 status of CTCs from mCRPC patients. Consequently, cabazitaxel might be a valid treatment option for patients with AR-V7-positive CTCs.. Tools are needed to select specific treatments for specific patients at specific times. The presence of the gene AR-V7 in CTCs has been associated with resistance to anti-androgen receptor treatments. We investigated whether this holds true for cabazitaxel, but we found cabazitaxel to be effective independent of the presence of AR-V7.

Topics: Aged; Humans; Male; Neoplastic Cells, Circulating; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids

The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC.. Data from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾ 50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel.. From the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase.. Our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Multivariate Analysis; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

Cabazitaxel is a novel taxane that is approved for use in metastatic castration-resistant prostate cancer based on the Phase III TROPIC study, which showed improved overall survival with cabazitaxel/prednisone versus mitoxantrone/prednisone. A global early-access program was initiated in order to provide early access to cabazitaxel in docetaxel-pretreated patients and to obtain real-world data.. We report interim safety results from an Italian prospective, single-arm, multicenter, open-label trial of 218 patients receiving cabazitaxel 25 mg/m2 every 3 weeks plus prednisolone 10 mg/day, until disease progression, unacceptable toxicity, investigator's decision or death.. Patients completing treatment received a median of six cabazitaxel cycles. The most common grade 3/4 adverse events were neutropenia (33.9%), leukopenia (15.6%), anemia (6%) and asthenia (6%). No peripheral neuropathy or nail disorders were observed.. These results confirm that cabazitaxel has a manageable safety profile in daily clinical practice and support its use in patients with prostate cancer who progress during or after a docetaxel-based therapy.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Italy; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC).. Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT.. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients.. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

Topics: Aged; Antineoplastic Agents; Asian People; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Based on the TROPIC study results, cabazitaxel was approved for the management of metastatic castration-resistant prostate cancer (mCRPC) progressing on or after docetaxel.. This multi-centre program provided early access to cabazitaxel to patients with mCRPC before its commercialization. Safety data from 153 Spanish patients receiving cabazitaxel 25 mg/m(2) i.v. Q3W, plus oral prednisone/prednisolone 10 mg daily, are reported.. Median age of patients was 70 years (26.8% ≥ 75 years), 94.1 and 26.8% had bone and visceral metastasis, respectively. Most had an Eastern Cooperative Oncology Group ≤ 1 (88.9%) and had received a median of 8.0 cycles of last docetaxel treatment. The median of cabazitaxel cycles and cumulative dose were 6.0 (Interquartile range [IQR]: 4.0; 8.0) and 148.9 (IQR: 98.2; 201.4) mg/m(2), respectively. Adverse events (AEs) possibly related to cabazitaxel occurred in 143 (93.5%) patients. The most frequent grade ≥ 3 AEs were neutropenia (n = 25, 16.3%) and asthenia (n = 17, 11.1%). Febrile neutropenia and grade ≥ 3 diarrhea occurred in 5.2% of the patients each. There were five (3.3%) possibly treatment-related deaths, mainly infection-related. G-CSFs were used in 114 (74.5%) patients, generally as prophylaxis (n = 107; 69.9%). Grade ≥ 3 peripheral neuropathy and nail disorders were uncommon.. Cabazitaxel administration, in a real-world setting, is tolerated by Spanish patients with mCRPC, and the AEs are manageable.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisolone; Prostatic Neoplasms, Castration-Resistant; Spain; Taxoids

Cabazitaxel significantly improves overall survival (OS) versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone.. Updated TROPIC data (cut-off 10 March 2010) were used to compare 2-year survival between treatment groups and assess patient demographics and disease characteristics. Factors prognostic for survival ≥2 years were assessed. Pain and Eastern Cooperative Oncology Group performance status were evaluated in the overall patient population.. Median follow-up was 25.5 months. After 2 years, more patients remained alive following cabazitaxel than mitoxantrone [odds ratio 2.11; 95% confidence interval (CI) 1.33-3.33]. Treatment with cabazitaxel was prognostic for survival ≥2 years. Demographics/baseline characteristics were balanced between treatment arms irrespective of survival. Pain at baseline and pain response were comparable between treatment groups. Average daily pain performance index was lower for cabazitaxel versus mitoxantrone (all cycles; 95% CI -0.27 to -0.01; P = 0.035) and analgesic scores were similar. Grade ≥3 peripheral neuropathies were uncommon and comparable between treatment groups.. Cabazitaxel prolongs OS at 2 years versus mitoxantrone and has low rates of peripheral neuropathy. Palliation benefits of cabazitaxel were comparable to those of mitoxantrone. The study was registered with www.ClinicalTrials.gov (NCT00417079).

Topics: Aged; Aged, 80 and over; Analgesics; Antineoplastic Agents; Docetaxel; Humans; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Pain; Pain Measurement; Palliative Care; Peripheral Nervous System Diseases; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Survival; Survival Rate; Taxoids; Treatment Outcome

Prostate-specific antigen (PSA) kinetics, and more specifically a ≥ 30% decline in PSA within 3 months after initiation of first-line chemotherapy with docetaxel, are associated with improvement in overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). The objective of this analysis was to evaluate post-treatment PSA kinetics as surrogates for OS in patients receiving second-line chemotherapy.. Data from a phase III trial of patients with mCRPC randomly assigned to cabazitaxel plus prednisone (C + P) or mitoxantrone plus prednisone were used. PSA decline (≥ 30% and ≥ 50%), velocity, and rise within the first 3 months of treatment were evaluated as surrogates for OS. The Prentice criteria, proportion of treatment explained (PTE), and meta-analytic approaches were used as measures of surrogacy.. The observed hazard ratio (HR) for death for patients treated with C + P was 0.66 (95% CI, 0.55 to 0.79; P < .001). Furthermore, a ≥ 30% decline in PSA was a statistically significant predictor of OS (HR for death, 0.52; 95% CI, 0.43 to 0.64; P < .001). Adjusting for treatment effect, the HR for a ≥ 30% PSA decline was 0.50 (95% CI, 0.40 to 0.62; P < .001), but treatment remained statistically significant, thus failing the third Prentice criterion. The PTE for a ≥ 30% decline in PSA was 0.34 (95% CI, 0.11 to 0.56), indicating a lack of surrogacy for OS. The values of R(2) were < 1, suggesting that PSA decline was not surrogate for OS.. Surrogacy for any PSA-based end point could not be demonstrated in this analysis. Thus, the benefits of cabazitaxel in mediating a survival benefit are not fully captured by early PSA changes.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Drug Resistance, Neoplasm; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mitoxantrone; Neoplasm Metastasis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids

Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy.. Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC).. The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase. The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively.. A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed.

Topics: Aged; Alkaline Phosphatase; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biomarkers, Tumor; Docetaxel; Drug Administration Schedule; Hemoglobins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mitoxantrone; Models, Statistical; Multivariate Analysis; Nomograms; Organoplatinum Compounds; Pain; Predictive Value of Tests; Prednisone; Prognosis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Sensitivity and Specificity; Taxoids; Treatment Outcome

Serum testosterone level is a potential prognostic marker for castration-resistant prostate cancer. However, its role as a prognostic marker in cabazitaxel chemotherapy remains unclear. This study aimed to elucidate the clinical significance of serum testosterone levels before cabazitaxel chemotherapy.. This single-institution, retrospective study included 47 patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel therapy. Serum testosterone levels were measured before the initiation of cabazitaxel therapy.. Progression-free survival and overall survival (OS) were not significantly different between patients with high and low serum testosterone levels. Analysis of patients aged <70 years revealed that those with high serum testosterone levels (total testosterone level > 0.055 ng/mL) had significantly longer OS than those with low serum testosterone levels (total testosterone level < 0.055 ng/mL, p = 0.012). Multivariate analysis revealed that low serum testosterone levels (hazard ratio [HR] = 11.874, 95% confidence interval [CI] 2.076-67.953, p = 0.005) and high prostate-specific antigen levels (HR = 18.051, 95% CI 2.462-132.347, p = 0.004) in the pretreatment phase were independent prognostic factors for OS in patients receiving cabazitaxel therapy.. Serum testosterone level may be a prognostic marker for cabazitaxel therapy in patients with mCRPC who are younger than 70 years, and high serum testosterone levels may lead to longer survival.

Topics: Docetaxel; Humans; Male; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Testosterone; Treatment Outcome

The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC.. We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models.. We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression.. Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting AURKB and KIF20A.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Early Detection of Cancer; Humans; Male; Mice; Pimozide; Prostatic Neoplasms, Castration-Resistant; Taxoids

Cabazitaxel is a next-generation taxane that can prolong overall survival after docetaxel treatment in patients with metastatic castration-resistant prostate cancer. However, the efficacy of cabazitaxel varies among these patients. The clinical indicators of the prognosis after cabazitaxel treatment were analyzed.. A retrospective review of patients who received cabazitaxel between February 2015 and June 2021 was performed. All patients had metastatic castration-resistant prostate cancer. Prognostic factors for prostate-specific antigen progression-free and overall survival were analyzed by Cox proportional-hazards analysis and the log-rank test.. The study comprised 57 patients who received cabazitaxel (median 4 cycles, range 1-27) at a starting dose of 15-25 mg/m. Previous androgen receptor-axis-targeted therapy was the only risk factor for biochemical progression. Poor performance status, anemia, and high neutrophil-lymphocyte ratio were risk factors for poor prognosis in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel. These risk factors seem useful for identifying patients with survival benefit from cabazitaxel treatment.

Topics: Disease-Free Survival; Humans; Japan; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

This study investigated the efficacy of docetaxel (DOC) and cabazitaxel (CBZ) and examined the factors associated with the prognosis of patients with castration-resistant prostate cancer (CRPC) receiving DOC-CBZ sequential treatment in Japanese real-world data.. We retrospectively evaluated data for 146 patients who received DOC followed by CBZ. The correlations of prostate specific antigen (PSA) decrease rate and time to progression between DOC and CBZ treatment were examined. Combined progression-free survival (PFS) of DOC-CBZ and overall survival (OS) from the initiation of DOC and the diagnosis of CRPC were evaluated and compared between patients with high and low PSA levels at the start of DOC and CBZ treatment.. No correlations of PSA decrease rate and time to progression were observed between DOC and CBZ. The patients for whom DOC was started in higher PSA levels had significantly shorter combined PFS (p = 0.003) and OS from the initiation of DOC (p = 0.002). In patients who started DOC at high PSA levels, those who switched to CBZ at low PSA levels had longer OS than those who switched at high PSA levels (p = 0.048). The OS from CRPC of patients who started DOC at low PSA levels was significantly longer than those that started at high PSA levels (p = 0.030).. For patients for whom DOC was not effective, sequential CBZ might have change to be effective. The PSA levels at the start of DOC and CBZ might be a potential prognostic biomarker.

Topics: Docetaxel; Humans; Japan; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Using a hybrid cellular automaton with stochastic elements, we investigate the effectiveness of multiple drug therapies on prostate cancer (PCa) growth. The ability of Androgen Deprivation Therapy to reduce PCa growth represents a milestone in prostate cancer treatment, nonetheless most patients eventually become refractory and develop castration-resistant prostate cancer. In recent years, a "second generation" drug called enzalutamide has been used to treat advanced PCa, or patients already exposed to chemotherapy that stopped responding to it. However, tumour resistance to enzalutamide is not well understood, and in this context, preclinical models and in silico experiments (numerical simulations) are key to understanding the mechanisms of resistance and to assessing therapeutic settings that may delay or prevent the onset of resistance. In our mathematical system, we incorporate cell phenotype switching to model the development of increased drug resistance, and consider the effect of the micro-environment dynamics on necrosis and apoptosis of the tumour cells. The therapeutic strategies that we explore include using a single drug (enzalutamide), and drug combinations (enzalutamide and everolimus or cabazitaxel) with different treatment schedules. Our results highlight the effectiveness of alternating therapies, especially alternating enzalutamide and cabazitaxel over a year, and a comparison is made with data taken from TRAMP mice to verify our findings.

Topics: Androgen Antagonists; Animals; Drug Resistance, Neoplasm; Humans; Male; Mice; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Tumor Microenvironment

Docetaxel is a first-line chemotherapy drug for castration-resistant prostate cancer (CRPC); yet, some CRPC patients develop docetaxel drug resistance. Cabazitaxel is approved in the post-docetaxel treatment setting. However, recent studies suggested cross-resistance between the development of drug resistance and current treatments. In this study, we used docetaxel-resistant cell lines DU145/DTX50 and PC-3/DTX30 to measure the responses to cabazitaxel. Our findings demonstrated that docetaxel resistance could lead to cross-resistance to cabazitaxel. After docetaxel-resistant cells were treated with cabazitaxel, transcriptome analysis was performed, and the results were analyzed in combination with survival analysis and correlation analysis with Gleason score to screen the cross-resistance genes. The continuously increased expression of kinesin family member 14 (KIF14) was identified as the main cause of cross-resistance to cabazitaxel in docetaxel-resistant cells. Silencing the expression of KIF14 could restore the sensitivity of resistant PCa cells to docetaxel and cabazitaxel, attenuate proliferation and promote apoptosis of the resistant PCa cells. Notably, the depressed expression of KIF14 inhibited the phosphorylation of Akt located downstream. In summary, KIF14 mediates the cross-resistance between docetaxel and cabazitaxel, and targeting KIF14 could be an effective measurement for reversing docetaxel or cabazitaxel chemotherapy failure or enhancing the anti-tumor effects of docetaxel or cabazitaxel.

Topics: Antineoplastic Agents; Docetaxel; Drug Resistance, Neoplasm; Humans; Kinesins; Male; Oncogene Proteins; Phosphorylation; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt

When it comes to long-acting injections, lyotropic liquid crystals (LLCs) are considered as an effective and powerful drug delivery technology due to their low manufacturing and injection difficulty, consistent releasing behaviors with low burst, as well as broadly applicable drug loading capacity. However, monoolein and phytantriol, as two widely used LLC-forming materials, may give rise to tissue cytotoxicity and undesired immunological responses, which may hinder the wide application of this technology. In this study, we opted for two ingredients, phosphatidylcholine and α-tocopherol, as carriers on account of their nature-obtainable and biocompatible qualities. By changing the ratios between them, we conducted research on crystalline types, nanosized structures, viscoelastic differences, characteristics of releasing behaviors, and

Topics: Humans; Leuprolide; Liquid Crystals; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Pegfilgrastim is a long-acting, granulocyte colony-stimulating factor approved in Japan for the prevention of neutropenia caused by antineoplastic agents. Severe thrombocytopenia was reported with pegfilgrastim, however, the factors associated with thrombocytopenia are unclear. This study aimed to explore the factors associated with thrombocytopenia in patients with metastatic castration-resistant prostate cancer treated with pegfilgrastim for primary prophylaxis of febrile neutropenia (FN) with cabazitaxel.. This study included metastatic castration-resistant prostate cancer patients who received pegfilgrastim for primary prophylaxis of FN with cabazitaxel. The timing and severity of thrombocytopenia and factors associated with the reduction rate of platelets were examined in patients who received pegfilgrastim for the primary prevention of FN during the first course of cabazitaxel and by multiple regression analysis.. Thrombocytopenia was most common within 7 days of pegfilgrastim administration, with 32 cases of grade 1 and 6 cases of grade 2 as per the Common Terminology Criteria for Adverse Events version 5.0. Multiple regression analysis revealed that the reduction rate of platelets after pegfilgrastim administration was significantly positively correlated with monocytes. In contrast, the presence of liver metastases and neutrophils was significantly negatively correlated with the reduction rate of platelets.. Thrombocytopenia due to pegfilgrastim administered as primary prophylaxis for FN with cabazitaxel was most likely to occur within one week after pegfilgrastim administration, suggesting that monocytes, neutrophils, and liver metastases were associated with a reduction in platelets.

Topics: Antineoplastic Combined Chemotherapy Protocols; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Liver Neoplasms; Male; Polyethylene Glycols; Prostatic Neoplasms, Castration-Resistant; Recombinant Proteins; Thrombocytopenia

Prostate cancer is the second most common cancer type and the second most common cancer-related cause of death in men. Cabazitaxel, a next-generation taxane, shows favorable toxicity profile and is effective in docetaxel-resistant tumors. Despite initial responses, in most cases, prostate cancer patients acquire resistance to cabazitaxel. There is a need to identify molecular markers that can monitor and predict treatment response.. We performed transcriptional exosome profiling (Human Transcriptome Array-HTA 2.0) from the plasma of 19 patients with castration-resistant prostate cancer at baseline and in patients after one cycle of cabazitaxel (C1). The patients were stratified in two groups (responders and nonresponders) according to their clinical response to cabazitaxel. Gene set enrichment analysis and ingenuity pathway analysis platforms were used for gene and pathway analysis.. We detected molecular differences in the exosomes from two groups of patients (nonresponders vs. responders) at baseline in pathways related to prostate cancer, oncogenic signaling, cytoskeleton, and immune system. In nonresponders, we found enrichment of cytoskeleton related gene (Stathmin-1 and ITSN1) that have been associated with resistance to cabazitaxel. Monitoring of exosomal transcripts after the first cycle of treatment revealed changes in pathways associated with response to treatment.. Sequential transcriptional profiling of plasma-derived exosomes reveals differential expression of genes that may reflect resistance to cabazitaxel treatment and therapy response.

Topics: Exosomes; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids; Transcriptome; Treatment Outcome

Developing resistance to cabazitaxel is a major challenge in patients with docetaxel- and castration-resistant prostate cancer (CRPC) since it is frequently administered as a last resort. We have previously reported that CCL2 induces resistance to the antiproliferative effect of cabazitaxel in DU145-TxR/CxR prostate cancer cell lines. However, how CCL2 induces resistance to the antimigration effect of cabazitaxel remains unclear.. We established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR, which was confirmed to show docetaxel resistance. We performed migration assay and analyzed the expression of epithelial-mesenchymal transition markers using DU145-TxR/CxR with or without CCL2 silencing with small interfering RNA (siRNA) transfection.. Cabazitaxel inhibited the migration of DU145 cells through the inactivation of STAT3. A CCR2 (a specific receptor of CCL2) antagonist suppressed the migration of DU145-TxR and DU145-TxR/CxR cells under cabazitaxel treatment. Western blotting revealed that the CCR2 antagonist inhibited STAT3 phosphorylation in DU145-TxR and DU145-TxR/CxR cells under cabazitaxel treatment. CCL2 silencing with siRNA in DU145-TxR and DU145-TxR/CxR cells decreased migration through STAT3 and p38 inactivation. Furthermore, CCL2 activated AKT, and CCR2 antagonist inhibited AKT phosphorylation in DU145-TxR and DU145-TxR/CxR cells with recovery of sensitivity to cabazitaxel under cabazitaxel treatment.. The CCL2-CCR2 axis is a key contributor to resistance to the antimigration effect of cabazitaxel in prostate cancer cells. CCL2-CCR2 axis inhibition may be a potential therapeutic target against chemoresistant CRPC in combination with cabazitaxel.

Topics: Cell Line, Tumor; Chemokine CCL2; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Receptors, CCR2; RNA, Small Interfering

Enzalutamide, docetaxel, and cabazitaxel treatment resistance is a major problem in metastatic castration resistant prostate cancer (mCRPC), but the underlying genetic determinants are poorly understood. To identify genes that modulate treatment response to these drugs, we performed three genome-wide CRISPR/Cas9 knockout screens in the mCRPC cell line C4. The screens identified seven candidates for enzalutamide (BCL2L13, CEP135, E2F4, IP6K2, KDM6A, SMS, and XPO4), four candidates for docetaxel (DRG1, LMO7, NCOA2, and ZNF268), and nine candidates for cabazitaxel (ARHGAP11B, DRG1, FKBP5, FRYL, PRKAB1, RP2, SMPD2, TCEA2, and ZNF585B). We generated single-gene C4 knockout clones/populations for all genes and could validate effect on treatment response for five genes (IP6K2, XPO4, DRG1, PRKAB1, and RP2). Altered enzalutamide response upon IP6K2 and XPO4 knockout was associated with deregulation of AR, mTORC1, and E2F signaling, and deregulated p53 signaling (IP6K2 only) in C4 mCRPC cells. Our study highlights the necessity of performing individual validation of candidate hits from genome-wide CRISPR screens. Further studies are needed to assess the generalizability and translational potential of these findings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line; CRISPR-Cas Systems; Docetaxel; Early Detection of Cancer; GTPase-Activating Proteins; Humans; Male; Nitriles; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

The CARD trial was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received docetaxel and experienced disease progression within 1 year on an androgen receptor-axis-targeted therapy (ARAT). Subsequent treatment with cabazitaxel had improved clinical outcomes compared with an alternative ARAT. This study aims to confirm the effectiveness of cabazitaxel in real-world patients in Japan and compare their characteristics with those of patients from the CARD trial.. This was a post-hoc analysis of a nationwide post-marketing surveillance registering all patients who were prescribed cabazitaxel in Japan between September 2014 and June 2015. Included patients had received docetaxel and ≤ 1 year of an ARAT (abiraterone or enzalutamide) prior to receiving cabazitaxel or an alternative ARAT, as their third-line therapy. The primary effectiveness endpoint was the time to treatment failure (TTF) of the third-line therapy. Patients were matched (1:1) from the cabazitaxel and second ARAT arms based on propensity score (PS).. Of the 535 patients analysed, 247 received cabazitaxel and 288 the alternative ARAT as their third-line therapy, of which, 91.3% (n = 263/288) received abiraterone and 8.7% (n = 25/288) received enzalutamide as their second third-line ARAT. Patients in the cabazitaxel and second ARAT arms had TNM classification of M1 or MX in 73.3% and 68.1%, Gleason score of 8-10 in 78.5% and 79.2% and mean (standard deviation) serum PSA levels of 483 (1370) and 594 (1241) ng/mL, respectively. Initial cabazitaxel dose was ≤ 20 mg/m. Consistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial.

Topics: Docetaxel; Humans; Japan; Male; Product Surveillance, Postmarketing; Prostatic Neoplasms, Castration-Resistant

The aim of this study was to evaluate the prognostic value of 68 Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT in metastatic castration-resistant prostate cancer patients receiving second-line chemotherapy with cabazitaxel.. All patients with metastatic castration-resistant prostate cancer who underwent a PSMA PET/CT within 8 weeks before initiating the cabazitaxel treatment were retrospectively evaluated. The whole-body PSMA total tumor volume (PSMA-TV) was measured for each patient. Other factors such as prostate-specific antigen, hemoglobin, lactate dehydrogenase, and alkaline phosphatase were recorded. A log-rank cutoff finder was used to define the PSMA-TV optimal cutoff. Survival analyses were performed using Cox regression and Kaplan-Meier methods.. In total, 32 patients were included, receiving a median of 6 cycles of cabazitaxel (range, 2-10). After a median follow-up of 12 months, 28 patients presented disease progression, and 18 died. Baseline PSMA-TV presented a significant association with progression-free survival (PFS) and overall survival (OS; P = 0.035 and P = 0.002, respectively). Optimal PSMA-TV cutoffs were 515 mL for PFS and 473 mL for OS. Patients with low volume presented longer PFS and OS than those with high volume: median PFS, 21 versus 12 weeks, respectively (hazard ratio, 0.33; P = 0.017); and median OS, 24 versus 8.5 months, respectively (hazard ratio, 0.21; P = 0.002). On the multivariable analyses, PSMA-TV remained an independent predictor of OS ( P = 0.016).. Our results show that total tumor volume measured on PSMA PET/CT is a prognostic biomarker in patients treated with cabazitaxel. High PSMA-TV before treatment initiation is associated with shorter PFS and OS.

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Positron Emission Tomography Computed Tomography; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome; Tumor Burden

To determine the safety of cabazitaxel and predictors of severe neutropenia caused by cabazitaxel in a patient population that includes those with comorbidities.. Of 42 prostate cancer patients treated with cabazitaxel at Osaka Medical and Pharmaceutical University Hospital between September 2014 and June 2022, 33 were included in this study, whereas 6 patients who were outpatients and 3 who were discharged early within 7 days upon patient request were excluded. Logistic regression analysis was used to examine predictors of severe neutropenia.. Comorbidities such as hypertension, dyslipidemia, diabetes mellitus, cerebrovascular disease, chronic kidney disease, liver dysfunction, and cardiac disease did not affect the incidence of severe neutropenia in patients receiving cabazitaxel. The baseline platelet count and the dose of cabazitaxel were also suggested to be markers for the development of severe neutropenia.

Topics: Comorbidity; Humans; Hypertension; Male; Neutropenia; Platelet Count; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Topics: Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids

A 75-year-old man presented with macroscopic hematuria and a high serum prostate-specific antigen (PSA) level. Macroscopic hematuria had subsided by the time of consultation. The PSA level was 38.590 ng/ml, which, along with rectal examination and magnetic resonance imaging findings, led to the suspicion of prostate cancer. Transrectal needle biopsy of the prostate revealed intraductal carcinoma of the prostate (IDC-P). Computed tomography and bone scintigraphy were performed, and the prostate cancer was classified as cT2cN0M0. After 6 months of combined androgen blockade therapy, a radical prostatectomy was performed; however, PSA levels continued to increase, and the patient was diagnosed with castration resistant prostate cancer. Multiple bone metastases appeared 5 months after the initiation of abiraterone therapy. Three courses of docetaxel and two courses of cabazitaxel were administered, but the disease progression continued. The IDC-P was found to be positive for the BRCA2 mutation by BRACAnalysis® performed at the start of cabazitaxel therapy. To our knowledge, no other cases of BRCA2 mutation positive IDC-P have been reported in Japan. After we started administration of Olaparib, the patient's PSA level was lowered and the disease progression stopped.

Topics: Aged; BRCA2 Protein; Carcinoma, Intraductal, Noninfiltrating; Disease Progression; Hematuria; Humans; Male; Mutation; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant

The activation of toll like receptors (TLR) potentially affect the inflammatory tumor microenvironment and thus is associated with tumor growth or inhibition. Cabazitaxel (CAB) has been effectively used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the immune regulatory role of CAB in the tumor microenvironment is not clear. In this context, we for the first time assessed the immunotherapeutic role of CAB in the TLR3 signalling following activation of Poly I:C in mCRPC cells.. The cytotoxic and apoptotic effects of CAB with the induction of Poly I:C were determined by WST-1, Annexin V, acridine orange, RT-PCR analysis, ELISA assay and immunofluorescence staining in DU-145 mCRPC and HUVEC control cells. Our findings showed that CAB treatment with Poly I:C significantly suppressed the proliferation of DU-145 cells through the induction of apoptosis and caspase activation. Additionally, higher concentration of CAB mediated the activation of TLR3 via increased cytoplasmic and nuclear expression of TLR3, TICAM-1 and IRF-3 in mCRPC cells.. Co-treatment of CAB and Poly I:C was more effective in mCRPC cells with less toxicity in control cells. However, further investigations are required to elucidate the molecular mechanisms of TLRs signalling upon CAB treatment at the molecular level to further validate the immunotherapeutic efficacy of CAB in mCRPC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Docetaxel; Humans; Immunotherapy; Interferon Regulatory Factor-3; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Signal Transduction; Taxoids; Toll-Like Receptor 3; Tumor Microenvironment

Multiple life-prolonging therapies are available for metastatic castration-resistant prostate cancer (mCRPC). However, the optimal treatment strategy following progression through standard treatment with docetaxel, androgen receptor signaling inhibitor (ARSI) and cabazitaxel, remains unclear. We aimed to describe treatment patterns in men with mCRPC following progression on standard treatments and determine whether subsequent treatment choice impacts overall survival.. Clinicopathologic and treatment data were extracted from the electronic CRPC Australian Database (ePAD) for patients who had received docetaxel, ARSIs and cabazitaxel in any order. Data were analyzed to compare groups that did versus did not receive subsequent systemic therapy. Treatment sequences, median duration of treatment, and median overall survival (mOS) were reported for each treatment group.. Ninety-eight eligible patients were identified, with 51 receiving subsequent systemic therapy. Those who received further treatment were younger (68 vs. 71 years, p < .01) but did not have any other differences in clinicopathologic features compared to those who received no further treatment. Patients who received upfront docetaxel were more likely to proceed to subsequent treatment (p = .02). Subsequent systemic therapies varied, the most common being carboplatin-based regimens (n = 13, 25.5%) and many patients were rechallenged with ARSI (n = 10, 19.6%) or docetaxel (n = 6, 11.8%). There was no difference in mOS according to subsequent systemic therapy (p = .09).. This retrospective multicenter analysis demonstrates the variation in treatment sequences used for mCRPC in the real-world setting. In the absence of high quality, prospective evidence, our results suggest that subsequent treatment choice does not influence survival outcomes and the optimal choice is guided by individual patient and disease-related factors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Docetaxel; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome

Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor (AR) copy number (CN).. Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI.. Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24-5.12, p=0.011), AKR1C3 (HR=2.01, 1.06-3.81, p=0.031), AR (HR=2.70, 1.46-5.01, p=0.002), EPCAM (HR=3.75, 2.10-6.71, p< 0.0001), PSMA (HR=2.09, 1.19-3.66, p=0.01), MDK (HR=3.35, 1.83-6.13, p< 0.0001), and HPRT1 (HR=2.46, 1.44-4.18, p=0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97-31.22, p=0.05), AR (OR=8.71, 2.32-32.25, p=0.001), EPCAM (OR=7.26, 1.47-35.73, p=0.015), PSMA (OR=3.86, 1.10-13.50, p=0.035), MDK (OR=6.84, 1.87-24.98, p=0.004), and HPRT1 (OR=7.41, 1.82-30.19, p=0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 (p=0.05), EPCAM (p=0.02), and MDK (p=0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47-8.17], p=0.004).. Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis.. Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017.

Topics: Biomarkers, Tumor; Gene Dosage; Gene Expression; Humans; Male; Neoplastic Cells, Circulating; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

To assess the efficacy of novel therapeutic agents, such as androgen receptor axis-targeted agents (ARATs) and cabazitaxel, for relapse of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel in real-world practice, we performed a subanalysis using database from PROSTAT-BSI, a prospective observational study to evaluate the utility of software for quantifying bone metastases on bone scintigraphy.. Patients with clinically relapsed mCRPC after docetaxel treatment who received the new agents (NEW group) and those who did not (standard of care, SOC group) were included; patients who received ARAT before DOC treatment were excluded. Overall survival (OS) after docetaxel treatment was compared between the NEW and SOC groups.. Patients in the NEW group had significantly better OS from the start of docetaxel than those in the SOC group (the median OS in NEW and SOC was 28.9 months vs. 14.5 months, respectively). Furthermore, regardless of the time from androgen-deprivation therapy to the start of docetaxel at mCRPC, the NEW group had a better OS from relapse after docetaxel than the SOC group.. In clinical practice, OS of patients with relapse after docetaxel was significantly improved in the NEW group over the SOC group.

Topics: Aged; Aged, 80 and over; Androgen Receptor Antagonists; Antineoplastic Agents; Bone Neoplasms; Databases, Factual; Docetaxel; Humans; Japan; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Recurrence; Taxoids; Time Factors; Treatment Outcome

We aimed to evaluate relationships between clinical outcomes and explanatory variables by network clustering analysis using data from a post marketing surveillance (PMS) study of castration-resistant prostate cancer (CRPC) patients.. The PMS was a prospective, multicenter, observational study of patients with metastatic, docetaxel-refractory CRPC treated with cabazitaxel in Japan after its launch in 2014. Graphical Markov (GM) model-based simulations and network clustering in 'R' package were conducted to identify correlations between clinical factors and outcomes. Factors shown to be associated with overall survival (OS) in the machine learning analysis were confirmed according to the clinical outcomes observed in the PMS.. Among the 660 patients analyzed, median patient age was 70.0 years, and median OS and time-to-treatment failure (TTF) were 319 and 116 days, respectively. In GM-based simulations, factors associated with OS were liver metastases, performance status (PS), TTF, and neutropenia (threshold 0.05), and liver metastases, PS, and TTF (threshold 0.01). Factors associated with TTF were OS and relative dose intensity (threshold 0.05), and OS (threshold 0.01). In network clustering in 'R' package, factors associated with OS were number of treatment cycles, discontinuation due to disease progression, and TTF (threshold 0.05), and liver and lung metastases, PS, discontinuation due to adverse events, and febrile neutropenia (threshold 0.01). Kaplan-Meier analysis of patient subgroups demonstrated that visceral metastases and poor PS at baseline were associated with worse OS, while neutropenia or febrile neutropenia and higher number of cabazitaxel cycles were associated with better OS.. Neutropenia may be a predictive factor for treatment efficacy in terms of survival. Poor PS and distant metastases to the liver and lungs were shown to be associated with worse outcomes, while factors related to treatment duration were shown to positively correlate with better OS.

Topics: Aged; Febrile Neutropenia; Humans; Liver Neoplasms; Machine Learning; Male; Product Surveillance, Postmarketing; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Taxoids

Little is known about the redox-adapted cancer cells for understanding their pharmacologically targetable features and chemotherapeutic responses. Thus, we present the first in vitro redox adaptation model for metastatic prostate cancer (mPC), LNCaP-hydrogen peroxide resistant (LNCaP-HPR), with enhanced oxidative stress resistance accompanying poor Cabazitaxel response. After establishing, the cells were characterized by comparing the viability, death, oxidative stress, total glutathione (GSH) levels and the mRNA and protein levels of the redox-sensitive transcription factors responsible for the adaptation, Nrf-2, NF-κB and HIF-1α. Then, the apoptotic effect of Cabazitaxel was evaluated in LNCaP mPC, LNCaP-HPR and C4-2 metastatic castration-resistant (mCRPC) cells. In response to H

Topics: Humans; Male; NF-kappa B; Oxidation-Reduction; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

The purpose of this study was to investigate factors predicting the sensitivity to cabazitaxel therapy in metastatic castration-resistant prostate cancer (mCRPC) patients with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) alterations. This single-institution, retrospective study included 12 mCRPC patients with PTEN alterations who had received cabazitaxel therapy. Five patients (41%) responded to cabazitaxel therapy with a prostate-specific antigen (PSA) level decline of ≥30% from baseline, and all of them had responded to prior docetaxel therapy with a PSA decline of ≥30%. None of the patients with a poor response to prior docetaxel therapy responded well to cabazitaxel therapy. Of the seven patients who did not respond to cabazitaxel and whose PSA declined from baseline was <30%, five (71%) were also refractory to prior docetaxel therapy. The PSA responses to docetaxel and cabazitaxel were significantly correlated (p = 0.027). Kaplan-Meier analysis revealed that progression-free survival (PFS) for cabazitaxel was significantly shorter for prior docetaxel nonresponders (3.3 versus 9.1 months, p = 0.028). Multivariate analysis revealed that a poor response to prior docetaxel (PSA decline < 30%) (hazard ratio [HR] = 6.382, 95% confidence interval [CI] 1.172-34.750, p = 0.032) and baseline PSA of ≥20 ng/ml (HR = 33.584, 95% CI 2.332-483.671, p = 0.010) were independent prognostic factors for PFS with cabazitaxel therapy. These results demonstrate cross-resistance between docetaxel and cabazitaxel. The response to prior docetaxel therapy can influence the sensitivity to cabazitaxel therapy in mCRPC patients with PTEN alterations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Retrospective Studies; Taxoids; Treatment Outcome

Cabazitaxel significantly improves clinical outcomes compared with a second androgen receptor-targeted agent (ARTA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and an ARTA (abiraterone or enzalutamide), as demonstrated in the CARD trial (NCT02485691). We aimed to estimate healthcare costs avoided with the use of cabazitaxel as a third-line (3 L) treatment versus a second ARTA from a US payer perspective.. Model inputs were based on the CARD trial, published sources, and estimates of typical clinical care patterns by genitourinary oncologists (n = 3). Assessed time points were 6, 12, 18, and 24 months. Outcomes included progression-free survival (PFS), radiographic PFS (rPFS), and overall survival (OS); hospitalization and intensive care unit (ICU) days; and costs (reported in 2020 US dollar [USD] and converted into Euro) to manage symptomatic skeletal events (SSEs), adverse events (AEs), and end-of-life care.. At 18 months, in a cohort of 100 patients, the use of cabazitaxel was estimated to result in 9 more patients achieving rPFS, 2 more patients achieving PFS, and 17 more survivors versus a second ARTA. The costs of SSEs, AEs, and end-of-life care were $498,909 (€424,073), $276,198 (€234,768), and $808,785 (€687,468), respectively, for cabazitaxel and $627,569 (€533,434), $251,124 (€213,455), and $1,028,294 (€874,050), respectively, for a second ARTA. Cabazitaxel was estimated to be associated with a 21% reduction in both SSE management and end-of-life care costs. Hospitalization cost was $1,442,870 (€1,226,440) for cabazitaxel and $1,728,394 (€1,469,135) for a second ARTA, representing an estimated 17% reduction in these costs. Cabazitaxel, as compared with a second ARTA, was associated with 58 fewer hospitalization days and 2 fewer ICU days and was estimated to avoid $323,095 (€274,630, 17%) in total costs, driven by SSEs management and end-of-life care.. The use of cabazitaxel as a 3 L treatment after docetaxel and an ARTA in patients with mCRPC is estimated to result in clinical benefits (longer rPFS, PFS, and OS) and lower healthcare resource utilization (fewer hospitalization and ICU days), compared with a second ARTA.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome; United States

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Humans; Male; Polymorphism, Single Nucleotide; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome; Tubulin

Topics: Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Taxoids

Sarcopenia is a known predictor of overall survival in several diseases. We investigated the relationship between sarcopenia and outcome of treatment with cabazitaxel (CBZ) for castration-resistant prostate cancer (CRPC) by a retrospective analysis of 37 patients, who were given cabazitaxel at our hospital, from December 2014 to November 2020. The skeletal muscle mass was evaluated using the Psoas Muscle Mass Index (PMI: psoas major muscle area at the level of the third lumber vertebra (cm²)/height x height (m²)) through computed tomography images. The severe sarcopenia group (PMI＜4.96) showed lower levels of serum albumin, in comparison with the non-severe sarcopenia group (PMI≥4.96). Multivariate analysis identified PMI (odds ratio＝3.7; P＝0.023) as an independent factor associated with prostate specific antigen response to CBZ therapy. However, there was no significant difference in the overall survival between the severe and the non-severe sarcopenia groups (P＝0.1). Skeletal muscle mass might be closely correlated to the therapeutic response to CBZ, but not to the prognosis of patients with CRPC. Nutritional rehabilitation and exercises targeting sarcopenia for patients with prostate cancer should be considered.

Topics: Humans; Male; Prognosis; Prostatic Neoplasms, Castration-Resistant; Psoas Muscles; Retrospective Studies; Sarcopenia; Taxoids

Androgen ablation therapy is the standard of care for newly diagnosed prostate cancer (PC) patients. PC that relapsed after hormonal therapy, referred to as castration-resistant PC (CRPC), often presents with metastasis (mCRPC) and is the major cause of disease lethality. The few available therapies for mCRPC include the Taxanes Docetaxel (DTX) and Cabazitaxel (CBZ). Alas, clinical success of Taxanes in mCRPC is limited by high intrinsic and acquired resistance. Therefore, it remains essential to develop rationally designed treatments for managing therapy-resistant mCRPC disease. The major effect of Taxanes on microtubule hyper-polymerization is a prolonged mitotic block due to activation of the Spindle Assembly Checkpoint (SAC). Taxane-sensitive cells eventually inactivate SAC and exit mitosis by mitotic catastrophe, resulting in genome instability and blockade of proliferation. Resistant cells remain in mitotic block, and, upon drug decay, resume mitosis and proliferation, underlying one resistance mechanism. In our study we explored the possibility of forced mitotic exit to elevate Taxane efficacy. Inactivation of the SAC component, mitotic checkpoint kinase Mps1/TTK with a small molecule inhibitor (Msp1i), potentiated efficacy of Taxanes treatment in both 2D cell culture and 3D prostasphere settings. Mechanistically, Mps1 inhibition forced mitotic catastrophe in cells blocked in mitosis by Taxanes. Androgen receptor (AR), the main driver of PC, is often mutated or truncated in mCRPC. Remarkably, Mps1i significantly potentiated CBZ cytotoxicity regardless of AR status, in both AR-WT and in AR-truncated CRPC cells. Overall, our data demonstrate that forced mitotic exit by Mps1 inhibition potentiates Taxanes efficacy. Given that several Mps1i's are currently in different stages of clinical trials, our results point to Mps1 as a new therapeutic target to potentiate efficacy of Taxanes in mCRPC patients.

Topics: Androgens; Bridged-Ring Compounds; Cell Cycle Proteins; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Receptors, Androgen; Taxoids

Since multiple oncological treatment options in metastatic castration-resistant prostate cancer (mCRPC) are available, optimal sequencing of therapies are under investigation. However, the efficacy of Cabazitaxel (CAB) in fourth and later lines of therapy is rarely investigated.. Fifty three patients with mCRPC treated with CAB in fourth line or later were included in our retrospective study, which involved eight uro-oncology centers in Germany. Clinical and tumor characteristics, as well as PSA-response rates were analyzed. Kaplan-Meier plots addressed overall survival (OS) and progression-free survival (PFS). Logistic regression models predicted risk factors of overall mortality (OM).. Of 53 patients, 79% (n=42), 19% (n=10) and 2% (n=1) received CAB in fourth, fifth and sixth line. A median of 4 cycles of CAB were administered. Median PSA at start of CAB was 199ng/ml (interquartile range (IQR) 70-869). In total, 89% had bone and 40% visceral metastases prior to the start of CAB. Moreover, 30% of patients received Docetaxel in first line therapy for mCRPC. Most frequent sequence of therapy was abiraterone followed by docetaxel and followed by enzalutamide. Overall, median PSA-response rate was -20% (IQR -80 to +10%). Patients with docetaxel in first line had a significantly better median PSA-response on CAB (-80 vs. 20%, P=0.03). Median OS, radiographic PFS and overall PFS were 14.8 (Confidence interval (CI): 11.0-20.8), 3.0 (CI: 2.9-4.0) and 2.9 (CI: 2.0-3.3) months, respectively. In multivariable analyses, visceral metastases, PSA >100ng/ml, ISUP4+5 and later administration of Docetaxel were predictors of OM.. Real-world experiences indicate that favorable oncologic outcomes can be achieved with CAB especially regarding PSA-response and OS even in the fourth line or later in patients with mCRPC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Treatment Outcome

Androgen receptor splice variant-7 (AR-V7) expression in circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) is associated with abiraterone and enzalutamide resistance. We determine whether cabazitaxel (CBZ) is equally effective in AR-V7-positive and -negative CRPC and whether AR-V7-positive patients retain CBZ sensitivity. This is the first prospective, open-label, Asian validation study of CBZ in Japanese patients with mCRPC after docetaxel (n = 48; four CBZ cycles; 2017-2020, Juntendo University Hospitals). Primary endpoint was prostate-specific antigen response rate (PSA-RR); secondary endpoints included overall survival (OS), bone scan index (BSI) PSA-RR (≥ 50% decline from baseline) for CTC-/ARV7-, CTC+ /ARV7-, and CTC +/ARV7+ groups. PSA-RR ≥ - 30% was 38% (18/48) and ≥ - 50% was 26% (12/48). BSI-change rate ≥ - 30% was 19% (9/41) and ≥ - 50% was 17% (8/41). Median OS was 13.7(12.2-18.9) months. PSA decline in early CBZ treatment associated with OS (p = 0.00173). BSI decline associated with OS (p = 0.0194). PSA-RR(≥ 50%) was 43%(6/14) in CTC-/ARV7-, 19%(5/26) in CTC+ ARV7-, and 12%(1/8) in CTC+/ARV7+ ( p > 0.05). AR-V7 in CTCs at baseline not associated with OS. AR-V7 was not associated with CBZ resistance in CTCs. Reductions in BSI and PSA in early stages of CBZ treatment may predict OS.

Topics: Androgens; Docetaxel; Humans; Male; Neoplastic Cells, Circulating; Nitriles; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Tomography, X-Ray Computed

Metastatic castration-resistant prostate cancer (mCRPC) patients with positive AR-V7 expression in their circulating tumour cells (CTCs) rarely derive benefit from abiraterone and enzalutamide.. We performed a prospective, multicenter, single arm phase II clinical trial (CABA-V7) in mCRPC patients previously treated with docetaxel and androgen deprivation therapy.. In this trial, we investigated whether cabazitaxel treatment resulted in clinically meaningful PSA response rates in patients with positive CTC-based AR-V7 expression and collected liquid biopsies for genomic profiling.. Cabazitaxel was found to be modestly effective, with only 12% of these patients obtaining a PSA response. Genomic profiling revealed that CTC-based AR-V7 expression was not associated with other known mCRPC-associated alterations. CTC-based AR-V7 status and dichotomised CTC counts were observed as independent prognostic markers at baseline.. AR-V7 positivity predicted poor overall survival (OS). However, cabazitaxel-treated AR-V7 positive patients and those lacking AR-V7 positivity, who received cabazitaxel as standard of care, appeared to have similar OS. Therefore, despite the low response rate, cabazitaxel may still be an effective treatment in this poor prognosis, AR-V7 positive patient population.

Topics: Androgen Antagonists; Humans; Male; Neoplastic Cells, Circulating; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen

We report the case of a 74-year-old man with metastatic castration-resistant prostatic cancer (CRPC), who underwent treatment with cabazitaxel. Initially, he underwent docetaxel treatment for 2 years and exhibited severe neuropathy in his hands caused by its toxicity. As a result, we replaced docetaxel with cabazitaxel. On receiving 100% of the dose of cabazitaxel in the first course, febrile neutropenia (FN) was observed on the seventh day. However, he soon recovered from the FN and we began relative dose intensity (RDI) treatment with an adequate dose-volume and interval of treatments. He was successfully administered 51 cabazitaxel treatment courses without severe adverse effects. Cabazitaxel is a highly effective drug used as second-line chemotherapy following docetaxel, and it causes fewer adverse effects compared with docetaxel. Cabazitaxel may be a suitable alternative for outpatient treatment. Given that the patient in this case had a long overall survival of more than 3.5 years and received over 50 courses of cabazitaxel, it is crucial for RDI to be taken very seriously.

Topics: Aged; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

To investigate real-world haematological toxicity, overall survival (OS) and the treatment characteristics of docetaxel and cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC).. This retrospective claims data study followed patients with mCRPC receiving cabazitaxel or docetaxel from their first chemotherapy infusion. Haematological toxicities were measured using treatment codes and inpatient diagnoses. OS was estimated using the Kaplan-Meier method. A multivariable Cox regression analysis was used to identify OS predictors.. Data from 539 patients administered docetaxel and 240 administered cabazitaxel were analysed. Regarding adverse events, within 8 months of treatment initiation, some kind of treatment for haematological toxicity was documented in 31% of patients given docetaxel and in 61% of patients given cabazitaxel. In the same period, hospitalization associated with haematological toxicity was documented in 11% of the patients in the docetaxel cohort and in 15% of the patients in the cabazitaxel cohort. In the docetaxel cohort, 9.9% of patients required reverse isolation and 13% were diagnosed with sepsis during hospitalization. In the cabazitaxel cohort, the cumulative incidence was 7.9% and 15%, respectively. The median OS was reached at 21.9 months in the docetaxel cohort and, because of a later line of therapy, at 11.3 months in the cabazitaxel cohort. A multivariate Cox regression revealed that indicators of locally advanced and metastatic disease, severe comorbidities, and prior hormonal/cytotoxic therapies were independent predictors of early death.. Cabazitaxel patients face an increased risk of haematological toxicities during treatment. Together with their short survival time, this calls for a strict indication when using cabazitaxel in patients with mCRPC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Cabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown. With the advent of poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in partially overlapping indications with cabazitaxel, we aimed to determine cabazitaxel activity in men with mCRPC according to their DDR status.. This is a retrospective multicenter study that enrolled patients with mCRPC treated with cabazitaxel who had undergone DDR tumour tissue profiling. Patients with at least one deleterious germline or somatic alterations were considered DDR positive (DDR+). Each DDR + patient has been matched with a DDR negative (DDR-) from the same institution who underwent the same test. An exploratory cohort of patients found to be DDR + by liquid biopsy was also included. Prostate specific antigen (PSA) decline≥50% (PSA50), PSA progression-free survival (PFS, PSA-PFS), radiographic PFS (rPFS), clinical PFS or radiographic PFS (c/rPFS) and OS were evaluated.. Among 190 men (95 DDR+, 95 DDR-) with tissue sequencing, PSA50 was achieved with cabazitaxel in 29/92 (32%) and 33/92 (36%) in patients with DDR+ and DDR- (P = 0.64). The median rPFS was 5.33 months [95%CI 4.34-7.04] versus 5.75 months [95%CI 4.67-7.27] (P = 0.55). The median OS was 15.4 months [95%CI 12.16-26.6] and 11.5 months [95%CI 9.76-14.4] (P = 0.036), respectively. No PSA50 responses on cabazitaxel were observed in BRCA1/2 patients previously treated with PARPi (n = 10). Similar outcomes with cabazitaxel were observed in the liquid biopsy cohort (n = 63 DDR+).. Our study suggests that cabazitaxel is active in patients with mCRPC regardless of their DDR status, although its activity in men pretreated with a PARPi may be lower.

Topics: Antineoplastic Agents; DNA Repair; Humans; Male; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Platinum-based chemotherapy is not standard of care for unselected or genetically selected metastatic castration-resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined subanalysis of all patients with comprehensive next-generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourteen patients (47%) were DDR deficient (DDRd), of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDRd patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate-specific antigen (PSA) decline and objective radiographic response. In the wild-type BRCA2 subgroup, 35% had a >50% PSA decline (P = .006) and 16% radiographic response (P < .001). Median overall survival was 21 months for BRCA2mut patients vs 7 months (P = .041) for those with functional BRCA2. AVPC patients demonstrated comparable responses to non-AVPC, including a similar overall survival, despite the poor prognosis for this subgroup. In the scope of the registration of poly-(ADP)-ribose polymerase inhibitors (PARPi) for mCRPC, we provide initial insights on cross-resistance between PARPi and platinum compounds. By combining the literature and our study, we identified 18 patients who received both agents. In this cohort, only BRCA2mut patients treated with platinum first (n = 4), responded to both agents. We confirm that BRCA2 inactivation is associated with meaningful responses to carboplatin, suggesting a role for both PARPi and platinum-based chemotherapy in preselected mCRPC patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; BRCA2 Protein; Carboplatin; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Germ-Line Mutation; Humans; Kaplan-Meier Estimate; Male; Neoplasm Staging; Netherlands; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

To date, the optimal sequencing of life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unclear owing to a lack of prospective trials. This study aimed to evaluate the efficacy and safety of cabazitaxel (CBZ) treatment and examine the prognostic factors for oncological outcomes in patients with mCRPC who received CBZ after docetaxel (DOC).. This multi-institutional retrospective study included 44 patients with mCRPC who received CBZ. All enrolled patients had histologically confirmed prostate cancer (PCa) with distant metastases and had received DOC before CBZ administration. The primary endpoint was the oncological outcomes, including the overall (OS) and progression-free survival (PFS). The secondary endpoints were adverse events due to CBZ and rates of ≥30% reduction in prostate-specific antigen (PSA) levels.. The median follow-up period was 9.2 months (range, 0.2-34 months). During this time, 34 patients (77%) died of PCa. The median OS and PFS were 12.2 (range, 0.2-34 months) and 1.4 months (range, 0.4-17 months), respectively. According to the PSA decline rate, patients who achieved a ≥30% reduction in PSA levels had significantly longer OS than those who showed a <30% reduction in PSA levels (P = 0.002). Regarding the number of cycles of CBZ, patients who received ≥4 cycles of CBZ showed significantly longer OS than those who received <4 cycles of CBZ (P < 0.001). Patients who had visceral metastasis showed significantly shorter OS than those without visceral metastasis (P = 0.012).. This study demonstrated that CBZ was effective and safe in Japanese local patients in a real-world setting. Patients with mCRPC who received ≥4 cycles of CBZ showed a ≥30% reduction in the serum PSA levels, and did not have visceral metastasis might achieve longer OS.

Topics: Aged; Antineoplastic Agents; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids; Treatment Outcome

Visceral metastasis (VM), an important poor prognostic factor of prostate cancer (PC), is not commonly observed in castration sensitive status but is often observed after castration-resistant progression. However, the site, timing of emergence, and incidence of VM in castration-resistant patients have not yet been fully elucidated.. Demographic, surgical, pathological, and follow-up data of PC patients treated at Kanazawa University Hospital between January 2000 and December 2016 were retrospectively analyzed using their medical charts. From this data, risk factors of VM and survival of patients with VM were elucidated.. Of 1364 patients, 21 (1.5%) had VM at diagnosis. Of 179 (13.1%) castration-resistant patients, 55 experienced emergence of new VM during treatment course. Incidence of new VM, especially nonlung, such as liver and adrenal metastases, increased significantly in proportion with the number of prescribed treatments. Multivariate analysis revealed that T stage, M stage, age, and treatment history with androgen receptor (AR) signaling-targeted agents and/or taxanes significantly increased the risk of VM. Compared with the group with VM at diagnosis, survival after diagnosis of VM following treatment was significantly shorter.. Although sequential use of new AR signaling-targeted agents and taxanes for castration-resistant PC (CRPC) is a standard treatment strategy, it often results in development of VM. Elucidating the mechanisms of VM are essential to improve survival in patients with CRPC.

Topics: Aged; Aged, 80 and over; Androstenes; Benzamides; Docetaxel; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Risk Factors; Signal Transduction; Taxoids

The recent CARD study has shown that sequential use of androgen receptor (AR)-targeted therapies is associated with worse outcomes when compared with cabazitaxel chemotherapy. Here we argue that this accounts for the majority of patients previously treated with an AR-targeted agent.

Topics: Androgen Antagonists; Antineoplastic Agents; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Taxoids

The aim of our study was to evaluate the cost-effectiveness of cabazitaxel versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel who had progression within 12 months while receiving an alternative inhibitor (abiraterone or enzalutamide) from a US payer's perspective.. To conduct the cost-effectiveness analysis, a Markov decision model was established. Three health states (progression-free survival (PFS), progressive disease (PD) and death) were included, and the incremental cost-effectiveness ratio (ICER) was regarded as the primary endpoint. The willingness-to-pay (WTP) threshold was set at $100,000.00/quality-adjusted life year (QALY), and discounted rates were set at 3% annually. Efficacy data were derived from the CARD trial and Weibull distribution curves were modeled to fit the survival curves. The robustness of the analysis was tested with a series of one-way sensitivity analyses and probabilistic sensitivity analyses.. Overall, the incremental effectiveness and cost of cabazitaxel versus androgen-signaling-targeted inhibitors (ASTIs) were 0.16 QALYs and $49,487.03, respectively, which yielded an ICER of $309,293.94/QALY. Our model was mostly sensitive to the duration of PFS in the cabazitaxel group, cost of cabazitaxel and utility of the PFS state. At a WTP threshold of $100,000.00/QALY, cabazitaxel was the dominant strategy in 0% of the simulations.. Cabazitaxel is unlikely to be a cost-effective treatment option compared with ASTIs in patients with mCRPC previously treated with docetaxel who had progression within 12 months while receiving ASTIs.

Topics: Androstenes; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Docetaxel; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Male; Prognosis; Prostatic Neoplasms, Castration-Resistant; Quality-Adjusted Life Years; Survival Rate; Taxoids

Cabazitaxel is used to treat patients with metastatic castration-resistant prostate cancer progressing after docetaxel. It is prepackaged in 60 mg single-dose vials, a quantity much higher than the average prescribed dose, which leads to, substantial drug wastage (DW) and associated costs. To minimize DW we implemented a cost-saving, cohorting strategy where multiple patients scheduled to receive cabazitaxel (at a dose of 20mg/m

Topics: Cost Savings; Drug Costs; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Taxoids

Cabazitaxel prolongs survival in patients with metastatic castration-resistant prostate cancer in the postdocetaxel setting. We investigate the benefit of continuing cabazitaxel beyond 10 cycles in patients who are clinically responding without significant toxicity.. A comparison was made between patients who received cabazitaxel for >10 cycles and those who had ≤10 cycles. Overall survival (OS), prostate-specific antigen (PSA) response, alkaline phosphatase (ALP) changes and treatment-associated adverse events were evaluated.. The median OS was 9 months (range 0.75-59), with OS significantly higher in patients who received extended duration of treatment: 14 months (range 3-90) vs 7 months (range 1.3-21) in patients treated with 4-10 cycles (HR 0.28, 95% CI 0.1 to 0.74, p=0.01). PSA decline did not show a significant correlation with OS (PSA decline ≥50%, p=0.54). Furthermore, there was no significant difference in OS between patients who had a normal versus high ALP at baseline. There was no clear evidence of cumulative toxicity in those having >10 cycles.. A substantial proportion of patients with metastatic castration-resistant prostate cancer were able to receive more than 10 cycles of cabazitaxel without clinically relevant cumulative toxicity.

Topics: Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Prostate cancer is known to have a relatively good prognosis, but long-term hormone therapy can lead to castration-resistant prostate cancer (CRPC). Cabazitaxel, a second-generation taxane, has been used for the CRPC treatment, but its tolerance is an urgent problem to be solved. In this study, to elucidate the acquisition mechanism of the cabazitaxel-resistance, we established cabazitaxel-resistant prostate cancer 22Rv1 (Cab-R) cells, which exhibited ∼sevenfold higher LD50 against cabazitaxel than the parental 22Rv1 cells. Cab-R cells showed marked increases in nuclear accumulation of NF-E2 related factor 2 (Nrf2) and expression of Nrf2-inducible antioxidant enzymes compared to 22Rv1 cells, suggesting that Nrf2 signalling is homeostatically activated in Cab-R cells. The cabazitaxel sensitivity of Cab-R cells was enhanced by silencing of Nrf2, and that of 22Rv1 cells was reduced by activation of Nrf2. Halofuginone (HF) has been recently identified as a potent Nrf2 synthetic inhibitor, and its treatment of Cab-R cells not only suppressed the Nrf2 signalling by decreasing both nuclear and cytosolic Nrf2 protein levels, but also significantly augmented the cabazitaxel sensitivity. Thus, inhibition of Nrf2 signalling may be effective in overcoming the cabazitaxel resistance in prostate cancer cells.

Topics: Antineoplastic Agents, Hormonal; Antioxidants; Cell Survival; Drug Resistance, Neoplasm; Humans; Male; NF-E2-Related Factor 2; Prostatic Neoplasms, Castration-Resistant; Signal Transduction; Taxoids; Tumor Cells, Cultured

In the CARD study (NCT02485691), cabazitaxel significantly improved clinical outcomes versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen-signalling-targeted inhibitor. However, some patients received docetaxel or the prior alternative androgen-signalling-targeted inhibitor in the metastatic hormone-sensitive (mHSPC) setting. Therefore, the CARD results cannot be directly translated to a Japanese population.. Patients (N = 255) received cabazitaxel (25 mg/m2 IV Q3W, prednisone, G-CSF) versus abiraterone (1000 mg PO, prednisone) or enzalutamide (160 mg PO) after prior docetaxel and progression ≤12 months on the alternative androgen-signalling-targeted inhibitor. Patients who received combination therapy for mHSPC were excluded (n = 33) as docetaxel is not approved in this setting in Japan.. A total of 222 patients (median age 70 years) were included in this subanalysis. Median number of cycles was higher for cabazitaxel versus androgen-signalling-targeted inhibitors (7 versus 4). Clinical outcomes favoured cabazitaxel over abiraterone or enzalutamide including, radiographic progression-free survival (rPFS; median 8.2 versus 3.4 months; P < 0.0001), overall survival (OS; 13.9 versus 11.8 months; P = 0.0102), PFS (4.4 versus 2.7 months; P < 0.0001), confirmed prostate-specific antigen response (37.0 versus 14.4%; P = 0.0006) and objective tumour response (38.9 versus 11.4%; P = 0.0036). For cabazitaxel versus androgen-signalling-targeted inhibitor, grade ≥ 3 adverse events occurred in 55% versus 44% of patients, with adverse events leading to death on study in 2.7% versus 5.7%.. Cabazitaxel significantly improved outcomes including rPFS and OS versus abiraterone or enzalutamide and are reflective of the Japanese patient population. Cabazitaxel should be considered the preferred treatment option over abiraterone or enzalutamide in this setting.

Topics: Aged; Androstenes; Benzamides; Disease-Free Survival; Humans; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time.. CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355).. In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037).. Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Chemoradiotherapy; Docetaxel; Follow-Up Studies; Humans; Male; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Radium; Retrospective Studies; Survival Rate; Taxoids

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Combined Modality Therapy; Docetaxel; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Radium; Retrospective Studies; Survival Rate; Taxoids

The aim was to investigate the efficacy of prophylactic antibiotics for the prevention of febrile neutropenia (FN) during cabazitaxel therapy for castration-resistant prostate cancer (CRPC) with G-CSF. We retrospectively studied 443 cycles of cabazitaxel therapy given to 56 patients with CRPC at Keio University Hospital between May 2012 and August 2018. Statistical analysis was conducted to determine whether the combination of prophylactic G-CSF and antibiotics was more effective in preventing FN, compared with prophylactic G-CSF alone. Prophylactic PEG-G-CSF or G-CSF was administered in all 443 cycles. Only fluoroquinolones were used as prophylactic antibiotics and were administered in 328 cycles (74.0%). FN occurred in 5 cycles (1.1%). Prophylactic antibiotics were administered in 327 cycles (74.6%) in the FN-negative group and in only 1 cycle (20.0%) in the FN-positive group. Chi-square test indicated the incidence of FN was significantly lower in the group that received prophylactic antibiotics compared with the group that did not receive prophylactic antibiotics (P = 0.017). Compared with prophylactic G-CSF alone, prophylactic G-CSF and antibiotics significantly suppressed the occurrence of FN.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Febrile Neutropenia; Follow-Up Studies; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

In this study, we investigated the association between the early response of serum and hematological variables and the outcome of cabazitaxel therapy.. The medical records of 59 consecutive patients who had previously received docetaxel chemotherapy for the treatment of metastatic castration-resistant prostate cancer (CRPC) and who received cabazitaxel at our hospital between January 2011 and March 2020 were retrospectively reviewed and statistically analyzed.. The median follow-up period after cabazitaxel initiation was 15.2 months. The 30% prostate-specific antigen (PSA) response rate, median PSA progression-free survival period, and overall survival (OS) period were 45.8%, 4.3 months, and 22.6 months, respectively. Within 1 to 2 cycles of cabazitaxel, we were unable to identify hematological or serum kinetics that had a relationship with OS. Analysis of the variables after 3 cycles of cabazitaxel, however, revealed two factors, PSA decline > 30% (p = 0.016) and neutrophil-lymphocyte ratio (NLR) decline > 30% (p = 0.044), as the predictors of favorable outcome for OS. We established a prognostic model for predicting the OS period composed of these two factors, which exhibited distinctly separated OS curves (p = 0.004). The C-index of a model incorporating these two factors was 0.703.. This is the first study to demonstrate that PSA and NLR decline 3 cycles after the initiation of cabazitaxel were associated with favorable outcome in patients with CRPC. Also, 3 cycles of cabazitaxel might be necessary to assess the efficacy of cabazitaxel therapy.

Topics: Aged; Antineoplastic Agents; Docetaxel; Humans; Lymphocytes; Male; Middle Aged; Neutrophils; Prognosis; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids; Treatment Outcome

BACKGROUND Cabazitaxel is a second-generation taxane approved for patients with metastatic castration-resistant prostate cancer (CRPC). Although cabazitaxel improves overall survival when used following docetaxel chemotherapy, duration of the clinical response is relatively short, and few patients achieve a long-term response. CASE REPORT A 71-year-old man with prostate adenocarcinoma with an initial prostate-specific antigen (PSA) level of 4956 ng/ml, Gleason score 4+5 and cTxN0M1b was referred to our department for treatment. Several therapeutic approaches, including androgen deprivation therapy, with a combination of bicalutamide and a luteinizing hormone-releasing hormone analogue, and 4 sequential hormonal therapies including flutamide, estramustine, enzalutamide, and abiraterone, all failed to prevent disease progression. Subsequently, after 5 cycles of docetaxel chemotherapy were also ineffective, cabazitaxel chemotherapy at a dose of 20 mg/m² together with prednisone and pegfilgrastim was initiated. The patient developed grade 4 thrombocytopenia during the first 4 cycles, and the dosage of cabazitaxel had to be tapered to 12.5 mg/m² by the fifth cycle. In subsequent cycles, the treatment was continued without grade 4 thrombocytopenia or any other toxicities ³grade 3. The patient achieved a long-term clinical response over 4 years and his PSA level continued to decrease, from 29.8 ng/ml at treatment initiation to a nadir of 2.0 ng/ml after the 60th cycle. CONCLUSIONS The present case is a rare example of a sustained response to low-dose cabazitaxel, and suggests its potential as a treatment option for metastatic CRPC patients. In our patient, this approach achieved a good clinical response with manageable toxicity over the long term.

Topics: Aged; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Docetaxel and cabazitaxel-based taxane chemotherapy are critical components in the management of advanced prostate cancer. However, their efficacy is hindered due to

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Biomarkers, Tumor; Cell Proliferation; Docetaxel; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids; Tumor Cells, Cultured

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo.. Cabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo.. The resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations.. ORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Cell Line, Tumor; Drug Synergism; Humans; Hyaluronic Acid; Lipids; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Recurrence, Local; Orlistat; Particle Size; Polymers; Prodrugs; Prostatic Neoplasms, Castration-Resistant; Taxoids; Xenograft Model Antitumor Assays

Prostate cancer (PCa) remains the second leading cause of cancer-related death among men. Taxanes, such as docetaxel and cabazitaxel are utilized in standard treatment regimens for chemotherapy naïve castration-resistant PCa. However, tumors often develop resistance to taxane chemotherapeutics, highlighting a need to identify additional therapeutic targets. Fatty acid-binding protein 5 (FABP5) is an intracellular lipid carrier whose expression is upregulated in metastatic PCa and increases cell growth, invasion, and tumor formation. Here, we assessed whether FABP5 inhibitors synergize with semi-synthetic taxanes to induce cytotoxicity in vitro and attenuate tumor growth in vivo.. PC3, DU-145, and 22Rv1 PCa cells were incubated with FABP5 inhibitors Stony Brook fatty acid-binding protein inhibitor 102 (SBFI-102) or SBFI-103 in the presence or absence of docetaxel or cabazitaxel, and cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay. Cytotoxicity of SBFI-102 and SBFI-103 was also evaluated in noncancerous cells. For the in vivo studies, PC3 cells were subcutaneously implanted into BALB/c nude mice, which were subsequently treated with FABP5 inhibitors, docetaxel, or a combination of both.. SBFI-102 and SBFI-103 produced cytotoxicity in the PCa cells. Coincubation of the PCa cells with FABP5 inhibitors and docetaxel or cabazitaxel produced synergistic cytotoxic effects in vitro. Treatment of mice with FABP5 inhibitors reduced tumor growth and a combination of FABP5 inhibitors with a submaximal dose of docetaxel reduced tumor growth to a larger extent than treatment with each drug alone.. FABP5 inhibitors increase the cytotoxic and tumor-suppressive effects of taxanes in PCa cells. The ability of these drugs to synergize could permit more efficacious antitumor activity while allowing for dosages of docetaxel or cabazitaxel to be lowered, potentially decreasing taxane-resistance.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Growth Processes; Cell Line, Tumor; Docetaxel; Drug Synergism; Fatty Acid-Binding Proteins; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; PC-3 Cells; Prostatic Neoplasms, Castration-Resistant; Taxoids; Xenograft Model Antitumor Assays

The sequential use of a number of new agents (NAs) have improved the overall survival (OS) of patients with metastatic castration-resistant prostate cancer whose disease progresses after docetaxel (DOC) treatment. The aim of this study was to assess the cumulative survival outcomes of different sequencing strategies by evaluating the individual data from published studies of patients treated with a post-DOC treatment sequence of 2 NAs.. The patients' individual data were analyzed to investigate whether different sequencing strategies lead to differences in OS.. We analyzed the data of 1099 evaluable patients. Among the patients treated with a second-line new hormone agent (NHA), median OS from the start of third-line treatment was significantly longer in the patients treated with cabazitaxel (CABA) than in those treated with abiraterone acetate or enzalutamide. Median cumulative OS (cumOS) from the start of second-line treatment was 21.1 months in the patients who received NHA then NHA, 22.1 months in those who received NHA then CABA, and 21.0 months in those who received CABA then NHA. Among the patients with a second-line progression-free survival of ≥6 months, median cumOS was significantly longer in patients who received CABA-including sequences than in those treated with NHA then NHA sequences (29.5 vs. 24.8 months; P = .03).. Our findings suggest that the sequential use of NAs with different mechanisms of action improves cumOS regardless of the order in which they are administered, thus supporting the hypothesis of cross-resistance between the 2 NHAs.

Topics: Abiraterone Acetate; Age Factors; Aged; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Neoplasm Grading; Nitriles; Observational Studies as Topic; Phenylthiohydantoin; Progression-Free Survival; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy.. We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival.. The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio [HR], 0.84; P = .530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR, 0.82; P = .650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR, 1.58; P = .384).. The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

Topics: Abiraterone Acetate; Aged; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Follow-Up Studies; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

The ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit in metastatic Castration Resistant Prostate Cancer (mCRPC) patients treated with Radium-223 dichloride (Ra-223) over placebo. Here we report clinical outcomes of Ra-223 treatment in a nonstudy population. In this prospective registry, patients from 20 Dutch hospitals were included prior to Ra-223 treatment. Clinical parameters collected included previous treatments and Adverse Events. Primary outcome was 6 months Symptomatic Skeletal Event (SSE)-free survival, while secondary outcomes included Progression-Free Survival (PFS) and Overall Survival (OS). Of the 305 patients included, 300 were evaluable. The mean age was 73.6 years, 90% had ≥6 bone metastases and 74.1% were pretreated with Docetaxel, 19.5% with Cabazitaxel and 80.5% with Abiraterone and/or Enzalutamide. Of all patients, 96.7% were treated with Ra-223 and received a median of 5 cycles. After a median follow-up of 13.2 months, 6 months SSE-free survival rate was 83%, median PFS was 5.1 months and median OS was 15.2 months. Six months SSE-free survival rate and OS were comparable with those reported in ALSYMPCA. "Previous Cabazitaxel treatment" and "bone-only metastases" were independent predictors of a shorter and longer PFS, respectively, while above-median LDH and "bone-only metastases" were independent predictors of shorter and longer OS, respectively. Toxicity was similar as reported in the ALSYMPCA trial. These results suggest that in a nonstudy population, Ra-223 treatment is well-tolerated, equally effective as in the ALSYMPCA population and that patients not previously treated with Cabazitaxel benefit most from Ra-223.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Benzamides; Bone Neoplasms; Chemoradiotherapy; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Outcome Assessment, Health Care; Phenylthiohydantoin; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Radium; Registries; Taxoids

This multi-institutional study aimed to identify prognostic factors for cabazitaxel treatment of castration-resistant prostate cancer (CRPC). This study included 74 Japanese patients with CRPC who were treated with cabazitaxel between 2014 and 2017. Associations between clinicopathological factors including serum markers and progression-free survival (PFS) and overall survival (OS) were investigated. On multivariate analysis, high Gleason score [≥9 vs. ≤7; hazard ratio (HR), 95% confidence interval (CI): 2.00 (1.01-4.34); P = 0.047], presence of pain [HR, 95% CI: 2.02 (1.14-3.58); P = 0.016], and lactate dehydrogenase (LDH) level [HR, 95% CI: 47.31 (3.79-577.49); P = 0.0019] were significantly associated with PFS. Similarly, number of docetaxel cycles [HR, 95% CI: 0.050 (0.0037-0.45); P = 0.0057], performance status [≥2 vs. 0; HR, 95% CI: 5.07 (1.57-16.24); P < 0.0001], and LDH level [HR, 95% CI: 2946 (50-420994); P = 0.0001] were significantly associated with OS. This study showed that LDH level is robustly prognostic for both PFS and OS in cabazitaxel chemotherapy for CRPC.

Topics: Aged; Humans; L-Lactate Dehydrogenase; Male; Prognosis; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carboplatin; Circulating Tumor DNA; Humans; Male; Middle Aged; Mutation; Prognosis; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins B-raf; Taxoids

Androgen receptor variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC) and has shown potential as a predictive biomarker in circulating tumour cells (CTCs) isolated from the bloodstream in terms of a liquid biopsy. Studies have shown that AR-V7 is a potential surrogate for selecting drug classes for systemic treatment by detecting nuclear AR-V7 by immunofluorescence or measuring AR-V7 messenger RNA by quantitative PCR. Here, we assessed the predictive value of AR-V7 detected by classical immunohistochemistry (IHC) for treatment response.. CTCs were isolated by cell separation by density gradient centrifugation from patients with metastatic CRPC (n = 26) before, while, and after undergoing a new therapy with chemotherapy (cabazitaxel or docetaxel) or antiandrogen (enzalutamide or abiraterone). CTCs were sequentially cytospun on object slides, and AR-V7 status was then detected by IHC based on a staining regime established on a 22Rv1 cell line with antibodies against CK8/18 und AR-V7.. AR-V7 status detected by IHC showed no predictive value for progression-free survival (PFS). Kaplan-Meier analysis revealed that there was no difference in PFS between patients found positive or negative for AR-V7.. AR-V7 detected by classical IHC has no predictive value for treatment response in the described setting. The future role of AR-V7 in CTCs as a biomarker in clinical routine remains elusive.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Humans; Male; Neoplastic Cells, Circulating; Prognosis; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset of resistance. In this study, the prostate cancer multistage murine model TRAMP and TRAMP-derived cells have been used to extensively characterize

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Humans; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Taxoids

Clinical trials have demonstrated the efficacy of several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC); however, real-world data on their use, survival effect, and safety are limited. Using electronic health record data from the Flatiron Health database, we studied real-world treatment patterns and health outcomes in patients with mCRPC.. We conducted a retrospective, non-interventional cohort analysis of electronic health record data of patients with confirmed mCRPC between January 2013 and September 2017. The primary objective was to describe real-world treatment patterns, including treatment type, duration, and sequencing. Secondary objectives included describing patient characteristics and clinical outcomes.. Of 2559 patients with mCRPC, 1980 (77%) received at least 1 line of life-prolonging therapy (abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). Of patients receiving first-line therapy, 49% received second-line therapy, and of these, 43% received third-line therapy. Abiraterone/prednisone and enzalutamide accounted for 65% of first-line therapies and 54% of second-line therapies. Docetaxel was the most common third-line therapy (24%). Back-to-back use of abiraterone/prednisone and enzalutamide was common. Radium-223 monotherapy use was 2% in the first-line setting, 3% in the second-line setting, and 8% in the third-line setting. The median overall survival was longer in patients who received life-prolonging therapies (23.7 months; 95% confidence interval: 22.3-25.1 months) than in those who did not (10.1 months; 95% confidence interval: 9.1-11.5 months).. These real-world insights on over 2500 patients with mCRPC supplement findings from randomized controlled trials and may help to inform clinical trial design, treatment guidelines, and clinical decision-making.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Follow-Up Studies; Humans; Male; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids; Tissue Extracts

Data on the safety and efficacy of cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer (CRPC) are limited. We report the safety (adverse drug reactions [ADRs]) and efficacy (overall survival [OS], time to treatment failure [TTF], and prostate-specific antigen [PSA] response rates) in patients aged <80 or ≥80 years treated with cabazitaxel for CRPC in clinical practice.. We performed post-hoc subgroup analyses of a Japanese post-marketing surveillance study involving 662 patients with CRPC treated with cabazitaxel between September 2014 and June 2016.. In patients aged <80 (n = 610) and ≥80 years (n = 49), median PSA at baseline was 168.7 and 109.0 ng/mL, and 86.7% and 83.7% of patients were previously treated with enzalutamide and/or abiraterone. ADRs (all grade) occurred in 77.2% and 79.6% of patients aged <80 and ≥80 years, with grade three/worse ADRs in 61.8% and 63.3% of patients. Hematologic toxicities were the most common grade three/worse ADRs, including neutropenia, febrile neutropenia, and anemia in both subgroups. No specific ADRs were observed in patients aged ≥80 years. The PSA response and median OS and TTF were 28.3%, 292 days, and 116 days in patients aged ≥80 years, and 29.7%, 319 days, and 125 days in patients aged <80 years.. Cabazitaxel could be a treatment option for CRPC in patients aged ≥80 years based on its safety and efficacy profiles. This is the first report to investigate the safety and efficacy of cabazitaxel in patients aged ≥80 years with CRPC.

Topics: Humans; Japan; Male; Product Surveillance, Postmarketing; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

This prospective study collected quality of life (QoL) and pain data during cabazitaxel treatment in patients with advanced metastatic or castration-resistant prostate cancer (mCRPC).. Functional Assessment of Cancer Therapy-Prostate (QoL) and Brief Pain Inventory-Short Form (pain) questionnaires were collected over 6 months.. In 61 patients with mCRPC (median age, 72 years) from 22 centers, metastatic sites were bones (97%), lymph nodes (36%), and visceral (20%); 25% received cabazitaxel in the second line, 29% in the third line, and 46% in the fourth line or beyond. All had been previously treated with docetaxel, except one with paclitaxel, and 75% also with abiraterone, enzalutamide, or both. The median cabazitaxel duration was 3.4 months. Forty-nine patients were evaluable for QoL and 44 for pain. QoL was improved in 37%, maintained in 35%, and deteriorated in 37%. In 27%, pain decreased ≥ 1 level and remained stable in 52%. A total of 34% lowered analgesic drug level. Prostate-specific antigen response ≥ 50% was observed in 11 (32.6%) patients, of whom 7 improved QoL and 1 was stable. At 6 months, 83.6% survived (95% confidence interval, 71.7%-90.8%). A total of 46% had ≥ 1 grade ≥ 3 adverse events, mainly anemia and neutropenia.. Although cabazitaxel was given as the third line and beyond for three-quarters of patients, over one-third had improved QoL and/or decreased pain during treatment.

Topics: Aged; Humans; Male; Pain; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids

A new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft models. Our results showed that Caba-780 was efficiently absorbed by DU145 and PC-3 cells and that the cytotoxicity of Caba-780 was significantly stronger than that of IR-780 and cabazitaxel. In addition, Caba-780 inhibited the migration and invasion of DU145 and PC-3 cells and promoted apoptosis by prolonging the G2 phase of the cell cycle. Further analysis indicated that Caba-780 could be used to effectively image tumor xenografts. At the same time, this drug inhibited the growth of tumors in vivo. Therefore, the new synthetic drug Caba-780 has potential applications in the diagnosis and treatment of CRPC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line; Cell Movement; Cell Survival; Fluorescent Dyes; Humans; Indoles; Male; Mice, Nude; Prostatic Neoplasms, Castration-Resistant; Taxoids

Disruption of the phenotypic landscape via epithelial-mesenchymal transition (EMT) enables prostate cancer cells to metastasize and acquire therapeutic resistance. Our previous studies demonstrated that cabazitaxel (CBZ) (second-generation Food and Drug Administration-approved taxane chemotherapy), used for the treatment of castration-resistant prostate cancer (CRPC), causes reversal of EMT to mesenchymal-epithelial transition (MET) and reduces expression of kinesin motor protein KIFC1 (HSET). The present study examined the effect of sequencing CBZ chemotherapy mediated MET on prostate tumor redifferentiation overcoming therapeutic resistance in models of advanced prostate cancer.. To examine the impact of androgens on the antitumor effect of CBZ, we used human prostate cancer cell lines with different sensitivity to androgens and CBZ, in vitro, and two human prostate cancer xenograft models in vivo. Tumor-bearing male mice (with either the androgen-sensitive LNCaP or the CRPC 22Rv1 xenografts) were treated with CBZ (3 mg/kg) alone, or in combination with castration-induced androgen-deprivation therapy (ADT) for 14 days.. Cell viability assays indicate that the presence of 5α-dihydrotestosterone (1 nM) confers resistance to CBZ in vitro. CBZ treatment in vivo induced MET in LNCaP-derived tumors as shown by increased E-cadherin and decreased N-cadherin levels. Sequencing CBZ after ADT improves tumor response in androgen-sensitive LNCaP, but not in CRPC 22Rv1 xenografts. Mechanistic dissection revealed a novel association between the androgen receptor and HSET in prostate cancer cells that is inhibited by CBZ in an androgen-dependent manner.. Our findings provide new insights into the phenotypic reprogramming of prostate cancer cells to resensitize tumors to CBZ action. This evidence is of translational significance in treatment sequencing (CBZ and ADT) towards improved therapeutic benefit in patients with lethal CRPC.

Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Cell Line, Tumor; Dihydrotestosterone; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Orchiectomy; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Random Allocation; Receptors, Androgen; Taxoids; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Minor Histocompatibility Antigens; Oligonucleotides, Antisense; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-bcl-2; RNA, Long Noncoding; Taxoids

The clinical course in metastatic castrate-resistant prostate cancer (mCRPC) can be complicated when patients have disease progression after prior treatment with second generation hormone therapy (second HT), such as enzalutamide or abiraterone. Currently, limited data exist regarding the optimal choice of chemotherapy for mCRPC after failing second generation hormone therapy. We sought to evaluate three common chemotherapy regimens in this setting.. We retrospectively identified 150 mCRPC patients with disease progression on enzalutamide or abiraterone. Of these 150 patients, 92 patients were chemo-naïve while 58 patients had previously received docetaxel chemotherapy before being started on second HT. After failing second HT, 90 patients were assigned for docetaxel-alone (group A), 33 patients received carboplatin plus docetaxel (group B), while 27 patients received cabazitaxel-alone (Group C). A favorable response was defined by more than or equal to 50% reduction in prostate-specific antigen from the baseline level after a complete course of chemotherapy. Survival outcomes were assessed for 30-month overall survival.. Patients in group (B) were 2.6 times as likely to have a favorable response compared to patients in group (A) (OR = 2.625, 95%CI: 1.15-5.99) and almost three times compared to patients in group (C) (OR = 2.975, 95%CI: 1.04-8.54) (P = .0442). 30-month overall survival was 70.7%, 38.9% and 30.3% for group (B), (A), and (C), respectively (P = .008). We report a Hazard Ratio of 3.1 (95% CI, 1.31-7.35; P = .0037) between patients in group (A) versus those in group (B) and a Hazard Ratio of 4.18 (95% CI, 1.58-11.06; P = .0037) between patients in group (C) compared to those in group (B) CONCLUSION: This data demonstrates improved response and overall survival in treatment-refractory mCRPC with a chemotherapy regimen of docetaxel plus carboplatin when compared to docetaxel alone or cabazitaxel alone. Further investigations are required.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carboplatin; Disease Progression; Docetaxel; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids; Treatment Failure

The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC).. Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel.. Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo.. Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Male; Mice; Naphthoquinones; Prostatic Neoplasms, Castration-Resistant; RNA, Messenger; Survivin; Taxoids; Xenograft Model Antitumor Assays

The purpose of this study was to identify previous treatments and biomarker profile features that prognosticate overall survival (OS) in patients with mCRPC receiving

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Taxoids

Automated bone scan index (aBSI) change (ΔBSI) after treatment and survival in men with prostate cancer remains unclear. We evaluated the correlation between ΔBSI after cabazitaxel and overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (CRPC).. We retrospectively enrolled 32 men with bone metastatic CRPC who had received cabazitaxel. The correlation between ΔBSI from baseline to 16 weeks after starting cabazitaxel and OS was analyzed by multivariate analysis.. Median age and time to CRPC were 70.7 years and 9.5 months, respectively. The median cycles of docetaxel before cabazitaxel were eight. Ten (31.2%) patients had visceral metastases at baseline. Median baseline prostate-specific antigen (PSA) was 123.0 ng/mL. The median aBSIs at baseline and 16 weeks after cabazitaxel were 3.2 and 4.4%, respectively. Improvements in aBSI and PSA after 16 weeks of cabazitaxel occurred in 7 (21.9%) and 12 patients (37.5%), respectively. There were no correlations between ΔBSI and OS (p = 0.55), but PSA change was significantly correlated with OS (p = 0.03) by multivariate analysis.. This study demonstrated that ΔBSI from baseline to16 weeks after starting cabazitaxel was not correlated with OS among men with bone metastatic CRPC. Further prospective studies may be warranted to confirm the limited utility of aBSI in this setting.

Topics: Aged; Aged, 80 and over; Bone Neoplasms; Correlation of Data; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids

Topics: Carboplatin; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

The interpretation of the presence of AR-V7 in circulating tumour cells (CTCs) in men with metastatic castration-resistant prostate cancer (mCRPC) remains to be elucidated. AR-V7 may hold promise as a predictive biomarker, but there may be prognostic impact of AR-V7 positivity as well. To investigate the clinical value of AR-V7, we determined whether AR-V7 detection in CTCs in patients with mCRPC is associated with CTC counts and survival.. Between December 2011 and January 2019, three prospective clinical trials collected clinical data of patients with mCRPC, who progressed after docetaxel and/or enzalutamide or abiraterone. Baseline (and follow-up) blood samples were withdrawn determining CTC count and AR-V7 expression. The majority of patients started cabazitaxel as the next line of treatment after AR-V7 characterisation.. A total of 127 samples were evaluable for the analysis of CTC count versus AR-V7 status. Although an association was observed between AR-V7 and CTC count in all patients with mCRPC (p = 0.017), no such association was found in the prognostic unfavourable subgroup of patients with ≥5 CTCs. After adjusting for clinical prognostic factors, AR-V7 expression in CTCs was not associated with overall survival (hazard ratio = 1.33, 95% confidence interval = 0.81-2.15, p = 0.25).. We found that AR-V7 expression in CTCs had no additional prognostic value in patients with mCRPC, mostly treated with cabazitaxel. In patients with mCRPC with a predefined worse prognosis of a higher CTC count (≥5), a predictive biomarker is an important unmet medical need. Prospective trials should investigate whether AR-V7 detection in CTCs may guide treatment selection for these adverse prognosis patients.

Topics: Aged; Biomarkers, Tumor; Blood Cell Count; Clinical Trials as Topic; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prognosis; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Retrospective Studies; Survival Analysis; Taxoids

Cabazitaxel (CBZ) is approved for docetaxel-resistant castration-resistant prostate cancer (CRPC). This retrospective study aimed at assessing the efficacy and prognostic markers of cabazitaxel treatment in Japanese CRPC patients.. The medical records of 44 consecutive Japanese patients with CRPC who started cabazitaxel at our Institution between January 2011 and February 2019 were reviewed and statistically analysed.. The median follow-up period after cabazitaxel initiation was 13.2 [interquartile range (IQR)=6.9-21.5] months. The objective response rate, median progression-free survival period, and median overall survival period (OS) were 45.5%, 4.3 months, and 20.7 months, respectively. On multivariate analysis, higher prostate-specific antigen (PSA; >100 ng/ml), lower haemoglobin (<10 g/dl), and lower number of prior docetaxel therapy cycles (<10) were predictors for shorter OS.. Patients with anemia, high PSA, and lower number of docetaxel therapy cycles might have shorter survival period from introduction of cabazitaxel therapy. In addition, PSA decline might still be a useful indicator as a predictor of prognosis of the metastatic CRPC patients treated with cabazitaxel.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Docetaxel; Humans; Japan; Male; Middle Aged; Neoplasms, Second Primary; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Factors; Taxoids; Treatment Outcome

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Humans; Male; Neoplasm Metastasis; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Cabazitaxel is a treatment of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure. The FUJI cohort aimed to confirm the real-life overall and progression-free survival (OS, PFS) and safety of cabazitaxel.. Multicentre, non-interventional cohort of French mCRPC patients initiating cabazitaxel between 2013 and 2015, followed 18 months.. Four hundred one patients were recruited in 42 centres. At inclusion, median age was 70, main metastatic sites were bones (87%), lymph nodes (42%) and visceral (20%). 18% had cabazitaxel in 2nd-line treatment, 39% in 3rd-line and 43% in 4th-line or beyond. All had prior docetaxel, and 82% prior abiraterone, enzalutamide or both. Median duration of cabazitaxel treatment was 3.4 months. Median OS from cabazitaxel initiation was 11.9 months [95% CI: 10.1-12.9]. In multivariate analyses, grade ≥ 3 adverse events, visceral metastases, polymedication, and >5 bone metastases were associated with a shorter OS. Main grade ≥ 3 adverse events were haematological with 8% febrile neutropenia.. Real-life survival with cabazitaxel in FUJI was shorter than in TROPIC (pivotal trial, median OS 15.1 months) or PROSELICA (clinical trial 20 vs 25 mg/m. It was registered with the European Medicines Agency EUPASS registry, available at www.encepp.eu, as EUPAS10391. It has been approved as an ENCEPP SEAL study.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bone Neoplasms; Docetaxel; Humans; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

To obtain routine clinical practice data on cabazitaxel usage patterns for patients with metastatic castration-resistant prostate cancer (mCRPC) and to describe physician-assessed cabazitaxel effectiveness, health-related quality of life (HRQoL) and safety.. CAPRISTANA was an international, observational cohort study examining cabazitaxel use for the treatment of patients with mCRPC. Effectiveness was assessed by overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF) and disease control rate. HRQoL was assessed using the Functional Assessment of Cancer Therapy-Prostate questionnaire (FACT-P) and the three-level European Quality of Life questionnaire (EQ-5D-3L). Safety was assessed by adverse event (AE) reporting.. A total of 189 patients were treated across 54 centres between April 2012 and June 2016. At baseline, 58.7% had ≥1 comorbidity, 93.7% had an Eastern Cooperative Oncology Group performance status ≤1, and 60.1% had a Gleason score at diagnosis of ≥8. Patients received a median of 6 cabazitaxel cycles; 84.7% received cabazitaxel as second-line therapy. The median OS, PFS and TTF were 13.2, 5.6 and 4.4 months, respectively. Cabazitaxel led to disease control in 52.9% of patients. HRQoL was maintained (40.3%) or improved (32.2%) in 72.5% of patients based on total FACT-P scores. Interestingly, 53.6% of patients reported pain improvement and a further 21.2% maintained pain control based on FACT-P prostate cancer-specific pain scores. The most common treatment-related grade ≥3 AEs were neutropenia (7.9%) and anaemia (2.1%).. Patients in CAPRISTANA treated with cabazitaxel had similar disease outcomes and safety profiles compared with large phase III clinical trials. Most patients had maintained or improved HRQoL scores; >70% of patients had maintained or improved pain control.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Follow-Up Studies; Humans; Male; Middle Aged; Neutrophils; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Survival Rate; Taxoids

Patients with cancer, including prostate cancer, often use dietary supplements, such as soy or isoflavones, before, during, or after therapy. There is little information about possible interactions between supplements and cancer chemotherapy. There are some reports suggesting enhancement by genistein of taxane chemotherapy for castrate-resistant prostate cancer (CRPC).. We investigated whether physiologically attainable concentrations of soy isoflavones (≤10 μM) interact with taxanes on growth inhibition of CRPC cells in vitro and in vivo in nude mice exposed via the diet, on microtubule disassembly in vitro, and on P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes.. Genistein, daidzein, and equol did not affect growth of VCaP, 22Rv1, C4-2, and PC-3 CRPC cells or growth inhibition of these cells by docetaxel and cabazitaxel. These isoflavones did not inhibit microtubule disassembly in vitro or inhibit the microtubule effects of taxanes and genistein did not bind substantially to microtubules. Genistein considerably inhibited P-glycoprotein-mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. However, dietary supplementation with genistein at 250 and 500 ppm did not affect the tumor growth inhibiting effect of docetaxel on 22Rv1 cells xenografted in nude mice.. Our results with relevant cell models and clinically achievable concentrations of soy isoflavones do not support the notion that genistein or other soy isoflavones can enhance the effects of taxane chemotherapy in CRPC cell and xenograft models. Yet, the inhibitory effects of genistein on drug efflux in 22Rv1 cells and on microsomal CYP3A4 activity raise the possibility that genistein can affect taxane effects on CRPC cells in other circumstances than those we studied, which merits further research.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Growth Processes; Cell Line, Tumor; Dietary Supplements; Docetaxel; Drug Synergism; Equol; Food-Drug Interactions; Genistein; Glycine max; Isoflavones; Male; Mice; Mice, Nude; Prostatic Neoplasms, Castration-Resistant; Random Allocation; Taxoids; Xenograft Model Antitumor Assays

Taxanes are a group of cytotoxic anti-cancer agents used in the treatment of solid tumours. The neurotoxic adverse effects of docetaxel and paclitaxel, including optic neuropathy, are well known. Cabazitaxel is a new generation taxane showing lesser drug resistance when compared with previous ones. Optic atrophy due to the use of cabazitaxel has not been previously reported. Herein, we report a patient with prostate cancer who developed optic atrophy after cabazitaxel treatment.

Topics: Adenocarcinoma; Antineoplastic Agents; Humans; Male; Middle Aged; Optic Atrophy; Prostatic Neoplasms, Castration-Resistant; Taxoids

Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC.. The present study included Japanese patients with metastatic prostate cancer whose serum testosterone levels during androgen-deprivation therapy were available. The antitumor outcomes when treated with enzalutamide, abiraterone, docetaxel, and cabazitaxel with clinicopathological parameters including serum testosterone levels during androgen-deprivation therapy, as well as prognoses including progression-free survival and overall survival, were examined.. Progression-free survival among men with higher serum testosterone level was superior to that among men with lower serum testosterone level when treated with enzalutamide. On the contrary, progression-free survival and overall survival among men with higher serum testosterone level were significantly inferior to those among men with lower serum testosterone level when treated with docetaxel and cabazitaxel, respectively.. The present study indicated distinct prognostic values of serum testosterone level when treated with androgen receptor axis-targeting agent and taxane chemotherapy for CRPC, suggesting that serum testosterone level may be useful predictive biomarker to navigate the appropriate therapy in patients with CRPC.

Topics: Aged; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Neoplasm Grading; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Testosterone

This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC).. The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017. The oncological outcomes and adverse events were compared between 16 (25.8%) and 46 (74.2%) men who were treated with standard 3-weekly and alternative 4-weekly regimens, respectively.. The prostate-specific antigen (PSA) response was comparable between the 3-weekly and 4-weekly regimens (median [interquartile range]: - 9.9% [- 64.5 to 13.0%] and - 30.7% [- 52.8 to 10.9%], P = 0.89), respectively. For patients on the 4-weekly regimen, the risks of progression (hazard ratio [HR], 95% confidence interval [CI] 1.27, 0.71-2.43, P = 0.44), treatment failure (HR, 95% CI 0.84, 0.48-1.55, P = 0.57) and any-cause mortality (HR, 95% CI 1.09, 0.58-2.17, P = 0.79) were comparable to those for patients on the 3-weekly regimen. The incidences of severe adverse events were also similar between the 3-weekly and 4-weekly regimens.. 3-weekly and 4-weekly regimens of cabazitaxel showed similar efficacy and safety profiles in a real-world clinical setting. These data suggest that a 4-weekly regimen may be acceptable for selected patients.

Topics: Aged; Drug Administration Schedule; Follow-Up Studies; Humans; Male; Patient Safety; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids; Treatment Outcome

Limited information is available to help physicians decide when to introduce cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC) patients. The objective of this study was to assess the optimal timing of cabazitaxel introduction.. The clinical outcomes of 66 mCRPC patients receiving cabazitaxel following failure of docetaxel were retrospectively analyzed.. Among the parameters possibly affecting the timing of cabazitaxel introduction, only an increased prostate-specific antigen (PSA) value from the diagnosis of CRPC had a significant impact on overall survival (OS) after the introduction of cabazitaxel. Furthermore, there was a significant correlation between the increased PSA value from the diagnosis of CRPC and the baseline PSA value at cabazitaxel introduction. Multivariate analysis showed that only the baseline PSA value at cabazitaxel introduction is an independent predictor of OS.. A comparatively low PSA value could be an alternative index suggesting the optimal timing for cabazitaxel introduction.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Administration Schedule; Humans; Japan; Kallikreins; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Time Factors; Treatment Outcome

Cabazitaxel (CBZ) chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) is believed to be palliative because the radiological response rate is low and a durable response is rare. Here, we describe a rare case of a patient with mCRPC who was treated with CBZ chemotherapy and showed a durable radiological response and a complete biochemical response.. We presented a rare case of a patient with mCRPC who was successfully treated with early CBZ chemotherapy. The early detection of metastasis using liquid biopsy enabled the introduction of early CBZ chemotherapy for docetaxel-resistant mCRPC.

Topics: Adenocarcinoma of Lung; Adult; Antineoplastic Agents; Docetaxel; Drug Resistance, Neoplasm; Early Detection of Cancer; Humans; Liquid Biopsy; Lung Neoplasms; Male; Neoplastic Cells, Circulating; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

Plasma androgen receptor (AR) copy number status has been identified as a potential biomarker of response in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR status in the context of cabazitaxel therapy is unknown.. Between September 2011 and January 2018, pretherapy plasma samples were collected from 155 patients treated with second- or third-line cabazitaxel at standard or reduced dose in different biomarker protocols. Droplet digital polymerase chain reaction was used to identify plasma AR gain and normal samples. The primary objective was to evaluate associations of plasma AR status with treatment outcome. In an exploratory analysis, a comparison between plasma AR and treatment type was investigated by incorporating updated data from our prior study of 85 post-docetaxel patients receiving abiraterone or enzalutamide.. We observed a shorter median overall survival (OS) and progression-free survival (PFS) in AR-gained compared to AR-normal patients (OS 10.5 versus 14.1 months, hazard ratio (HR) = 1.44, 95% confidence interval [CI] 0.98-2.13, P = 0.064 and PFS 4.0 versus 5.0 months, HR = 1.47, 95% CI 1.05-2.07, P = 0.024). In patients with mCRPC receiving second-line therapies, a significant treatment interaction was observed between plasma AR and cabazitaxel versus AR-directed therapies for OS (P = 0.041) but not PFS (P = 0.244). In an exploratory analysis, AR-gained patients treated with initial reduced dose of cabazitaxel had a significantly shorter median OS (7.3 versus 11.5 months, HR = 1.95, 95% CI 1.13-3.38, P = 0.016) and PFS (2.7 versus 5.0 months, HR = 2.27, 95% CI 1.39-3.71, P = 0.001).. Plasma AR status has a potential clinical utility in patients being considered for cabazitaxel. Validation of these findings in prospective trials is warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Disease-Free Survival; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

Interstitial pneumonitis is a rare reaction in a previously irradiated area of pulmonary or thoracic lesion after treatment with anticancer drugs such as taxanes.. A 66-year-old man presented with a fever and dyspnea after treatment with cabazitaxel for castration-resistant prostate cancer. He was treated with an intravenous broad-spectrum antimicrobial agent, however he complained of dyspnea and had a pulse oximetric saturation of 80% while breathing room air. The patients had been treated for bone metastases with 37.5 Gy to the thoracic spine (Th 7) as a local radiotherapy. Radiological images showed pulmonary interstitial opacities in the irradiated field of the both lungs. The steroid pulse therapy was started. The patient's dyspnea disappeared and the interstitial opacities had also improved.. This report is a case of interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy.

Topics: Administration, Intravenous; Aged; Antineoplastic Agents; Docetaxel; Drug Resistance, Neoplasm; Dyspnea; Follow-Up Studies; Glucocorticoids; Humans; Lung Diseases, Interstitial; Male; Methylprednisolone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Tomography, X-Ray Computed; Treatment Outcome

To evaluate the real-world safety and efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen.. This prospective multicenter observational study registered all patients with mCRPC treated with cabazitaxel following its launch in Japan in September 2014. Patient enrollment continued until at least 500 patients were enrolled. Adverse drug reactions (ADRs) were evaluated according to CTCAE ver. 4.0. Efficacy endpoints were assessed for up to 1 year, and included prostate specific antigen (PSA) response rates (defined as a decrease of ≥30% or ≥50% from baseline), overall survival (OS), and time to treatment failure (TTF).. A total of 660 mCRPC patients were enrolled across 316 centers by June 2016. Frequent ADRs (any grade) were neutropenia (49.1%), febrile neutropenia (18.0%) and anemia (15.0%). Most ADRs occurred in cycle 1. Neutropenia and febrile neutropenia were significantly less frequent in patients who received prophylactic granulocyte colony-stimulating factor. The PSA response rates for decrease of ≥30% or ≥50% from baseline were 28.1% and 17.5%, respectively, in patients with baseline PSA of ≥5 ng/ml. Median OS and TTF were 319 days (95% confidence interval: 293.0-361.0) and 116 days (95% confidence interval: 108.0-135.0), respectively.. This study of cabazitaxel in 660 Japanese patients treated in real-world settings, the largest study of cabazitaxel to date, demonstrated a safety profile that was generally consistent with those of pivotal clinical studies. Cabazitaxel was also effective in terms of the PSA response, OS, and TTF.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Docetaxel; Drug-Related Side Effects and Adverse Reactions; Granulocyte Colony-Stimulating Factor; Humans; Kallikreins; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Safety; Taxoids; Treatment Outcome

The objective of this study was to categorize prostate-specific antigen (PSA) response during cabazitaxel therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) into different patterns and to investigate the prognostic impact of the PSA response patterns.. We reviewed data from patients with mCRPC who had been treated with cabazitaxel therapy at four institutions belonging to Tokai Urologic Oncology Research Seminar. Patients eligible for this study had received at least three cycles of cabazitaxel treatment at three- or four-week intervals. The PSA response patterns were categorized as primary resistance (PR), response (RE), stabilization (ST), and fluctuating (FL). The overall survival (OS) was compared among the patterns.. Data from a total of 50 patients were analyzed in this study. The number of patients exhibiting PR, RE, ST and FL patterns were 18 (36%), 14 (28%), 12 (24%) and 6 (12%), respectively. The median (95% CI) OS of patients with PR and RE patterns was 10.7 (5.6-15.9) and 14.9 (6.8-23.0) months, respectively, and was not reached for patients with ST and FL patterns. The OS of patients with the FL pattern was significantly better than that of patients with PR (P = 0.012) and RE (P = 0.010) patterns.. There were some patients whose PSA were fluctuating during cabazitaxel therapy in patients with mCRPC. Because the prognosis of such patients was relatively good, the judgment to discontinue the cabazitaxel therapy after PSA rise followed by decrease should be made prudently.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Humans; Kallikreins; Male; Middle Aged; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids

To describe the patterns of second-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel treatment in a Spanish population, to identify the factors associated with those patterns, and to compare the efficacy and safety of the treatments most frequently administered.. Observational, prospective study conducted in patients with histologically or cytologically confirmed prostate adenocarcinoma; documented metastatic castration-resistant disease; progression after first-line, docetaxel-based chemotherapy with or without other agents.. Of the 150 patients recruited into the study, 100 patients were prescribed abiraterone acetate plus prednisone (AAP), 44 patients received cabazitaxel plus prednisone (CP), and 6 patients received other treatments. Age (odds ratio [OR] 1.06, 95% [confidence interval] CI 1.01 to 1.11) and not elevated lactate dehydrogenase (LDH) levels (OR 0.33, 95% CI 0.14 to 0.76) were independently associated with the administration of AAP. Treatment with AAP was associated with significantly longer clinical/radiographic progression-free survival (hazard ratio [HR] 0.57, 95% CI 0.38 to 0.85) and overall survival (OS; HR 0.40, 95% CI 0.21 to 0.76) compared to CP, while no significant differences between the treatments were found regarding biochemical progression-free survival (PFS; HR 0.78 [95% CI 0.49 to 1.24]). However, in a post-hoc Cox regression analysis adjusted for potential confounders there were not differences between AAP and CP in any of the time-to-event outcomes, including overall survival. We observed no new safety signals related to either regimen.. Second-line AAP for patients with mCRPC is the most common treatment strategy after progression with a docetaxel-based regimen. When controlling for potential confounders, patients receiving this treatment showed no differences in PFS and OS in comparison to those receiving CP, although these latter results should be confirmed in randomized controlled trials.

Topics: Abiraterone Acetate; Adenocarcinoma; Age Factors; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Docetaxel; Humans; Kaplan-Meier Estimate; L-Lactate Dehydrogenase; Male; Middle Aged; Multivariate Analysis; Pain; Prednisone; Progression-Free Survival; Proportional Hazards Models; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Spain; Taxoids; Treatment Outcome

To evaluate the safety and efficacy of a 2-weekly cabazitaxel schedule in patients with metastatic castration-resistant prostate cancer (mCRPC).. During the period October 2013 to February 2016, 43 patients with mCRPC were treated with cabazitaxel (16 mg/m. All patients had received prior docetaxel and 79.1% abiraterone acetate. At inclusion, 46.5% were aged >70 years and 27.9% had an Eastern Cooperative Oncology Group performance status ≥2. Six patients stopped treatment because of toxicity. Grade ≥3 toxicities were: asthenia (16.3%); neutropenia (11.6%); thrombocytopenia (9.3%); diarrhoea (7%), anaemia (4.7%), febrile neutropenia (4.7%) and haematuria (2.3%). In all, 52.4% achieved a ≥30% PSA response and 40.5% had a ≥50% PSA response. The median OS was 15.2 months.. This prospective pilot study suggests that cabazitaxel 16 mg/m² given 2-weekly has a manageable toxicity profile in docetaxel- and abiraterone acetate-pretreated patients with mCRPC. A prospective phase III trial comparing this regimen with the standard cabazitaxel regimen is planned to confirm these results.

Topics: Aged; Anemia; Antineoplastic Agents; Asthenia; Chemotherapy-Induced Febrile Neutropenia; Diarrhea; Disease-Free Survival; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Hematuria; Humans; Male; Neoplasm Metastasis; Pilot Projects; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Taxoids; Thrombocytopenia

Evaluation of responses to treatment for metastatic castration-resistant prostate cancer (mCRPC) remains challenging. Consensus criteria based on prostate-specific antigen (PSA) and clinical and radiologic biomarkers are inconsistently utilized. Circulating tumor cell (CTC) counts can inform prognosis and response, but are not routinely used.. To evaluate the use of biomarkers and trends in clinical decision-making in current mCRPC treatment.. A 23-part online questionnaire was completed by physicians treating mCRPC.. Results are presented as the proportion (%) of physicians responding to each of the options. We used χ. A total of 118 physicians (22.1%) responded. Of these, 69.4% treated ≥50 mCRPC patients/year. More physicians administered four or fewer courses of cabazitaxel (27.9%) than for docetaxel (10.4%), with no significant difference in the number of courses between bone-only disease and Response Evaluation Criteria in Solid Tumours (RECIST)-evaluable disease. Some 74.5% of respondents considered current biomarkers useful for monitoring disease, but only 39.6% used the Prostate Cancer Working Group (PCWG2) criteria in clinical practice. PSA was considered an important biomarker by 55.7%, but only 41.4% discarded changes in PSA before 12 wk, and only 39.4% were able to identify bone-scan progression according to PCWG2. The vast majority of physicians (90.5%) considered clinical progression to be important for switching treatment. The proportion considering biomarkers important was 71.6% for RECIST, 47.4% for bone scans, 23.2% for CTCs, and 21.1% for PSA. Although 53.1% acknowledged that baseline CTC counts are prognostic, only 33.7% would use CTC changes alone to switch treatment in patients with bone-only disease. The main challenges in using CTC counts were access to CTC technology (84.7%), cost (74.5%), and uncertainty over utility as a response indicator (58.2%).. A significant proportion of physicians discontinue treatment for mCRPC before 12 wk, raising concerns about inadequate response assessment. Many physicians find current biomarkers useful, but most rely on symptoms to drive treatment switch decisions, suggesting there is a need for more precise biomarkers.. In this report we analyse the results of a questionnaire evaluating tools for clinical decision-making completed by 118 prostate cancer specialists. We found that most physicians favour clinical progression over prostate-specific antigen or imaging, and that criteria established by the Prostate Cancer Working Group are not widely used.

Topics: Androstenes; Biomarkers, Tumor; Clinical Decision-Making; Disease Progression; Docetaxel; Humans; Male; Neoplasm Metastasis; Neoplastic Cells, Circulating; Practice Patterns, Physicians'; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Surveys and Questionnaires; Taxoids; Treatment Outcome; Tubulin Modulators

At the 2016 ASCO annual meeting, new data from two randomized phase III studies concerning taxane-based chemotherapy as a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC) were presented.. The focus is on the clinical impact of these data.. A group of German experts in the field of urogenital-oncologic expertise discussed the clinical impact with respect to the current data.. The study results support the current clinical data. They confirm the efficacy and safety of cabazitaxel beyond first-line therapy with docetaxel for patients with mCRPC.. Cabazitaxel is an important treatment option after docetaxel progression. With respect to the performance status of a patient, it is adequate to reduce the dosage to 20 mg/m

Topics: Docetaxel; Humans; Male; Neoplasms, Second Primary; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Benzamides; Drug Interactions; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel.. Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P < 0.0001). Overall survival (50% cut-off) was 23.3 months in responders and 16.0 months in non-responders (P = 0.068); corresponding data at the 30% cut-off are 21.7 and 16.0 months (P = 0.057). Overall, 55.4% of men experienced ≥ 1 adverse event, 59.6% of whom had a serious adverse event.. PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Disease-Free Survival; Humans; Kallikreins; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Topics: Antineoplastic Agents; Humans; Patient Selection; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Humans; Male; Neoplasms, Second Primary; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen. In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m² was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). An upfront dose-reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G-CSF was prescribed to all the patients. Grade ≥3 neutropenia and febrile neutropenia occurred in 21 patients (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated, with a median of 5 cycles (range 1-17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 and 15.0 months (95% CI 8.9-21.2), respectively. Waterfall plot analysis revealed that a prostate-specific antigen (PSA) decline >50% was noticed in n = 11 patients receiving cabazitaxel (26.8%). Univariate analysis revealed that poor performance status, PSA ≥100 ng/mL prior to cabazitaxel treatment, visceral metastasis, absence of grade 3/4 neutropenia during cabazitaxel therapy and neutrophil-lymphocyte ratio were significantly associated with shorter overall survival. Multivariate analysis revealed that poor performance status, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its hematological effects.

Topics: Aged; Aged, 80 and over; Humans; Male; Middle Aged; Neutropenia; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

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).. Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined.. A total of 267 patients received ADT → DOC → CABA (group 1), 183 patients ADT → DOC → ART → CABA (group 2), and 124 patients ADT → DOC → CABA → ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT ≤ 12 months, Gleason score of 8 to 10, clinical progression, and high prostate-specific antigen levels at mCRPC diagnosis were associated with worse OS. Prior receipt of ART did not influence activity of CABA.. OS appeared to increase with the number of life-extending therapies, with a sequence including DOC, CABA, and an ART providing the greatest OS benefit.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Databases, Factual; Disease Progression; Docetaxel; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Grading; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Survival Analysis; Taxoids; Treatment Outcome

The objective of this study was to conduct an indirect treatment comparison between cabazitaxel, abiraterone and enzalutamide to determine the clinical efficacy and safety of cabazitaxel relative to comparators in the treatment of patients with metastatic castrate-resistant prostate cancer who progress on docetaxel-based therapies.. A systematic literature review was conducted to inform the network meta-analysis of cabazitaxel, abiraterone and enzalutamide. Due to a lack of head-to-head trials, studies with a comparator arm of best supportive care were included in the analysis. Overall survival, progression-free survival, and adverse events were compared within both Bayesian and Frequentist frameworks. The ratios for survival outcomes were estimated using hazard ratios (HR), and the ratios for adverse events between groups were estimated using odds ratios (ORs); uncertainty was reported as 95% confidence (Frequentist) and credible (Baysesian) Intervals.. Three of thirteen trials identified for abstraction were relevant for analyses. Median overall survival was not statistically significantly different for abiraterone (HR = 1.04; 95% CI = 0.83-1.28) or enzalutamide (HR = 0.88; 95% CI = 0.69-1.11) when compared to cabazitaxel in the Bayesian analysis. Anaemia (OR = 3.71; 95% CI = 1.01-10.44), diarrhoea (OR = 16.60; 95% CI = 1.41-75.31) and haematuria (OR = 3.88; 95% CI = 1.03-10.09) were more likely to occur in the cabazitaxel group than the abiraterone group, while pyrexia risk was higher in cabazitaxel compared to enzalutamide (OR = 36.23; 95% CI = 1.14-206.40). Frequentist analyses produced similar results.. The scarcity of clinical studies and lack of a common comparator limited analyses. The adverse event results must be interpreted with caution as many were based on small numbers. The results from this analysis indicate comparable survival outcomes and adverse event profiles. As these pivotal studies may not reflect the contemporary treatment landscape and patient profiles, additional research, including head-to-head clinical trials and real world observational studies, should be conducted to further elucidate the beneficial effects of these therapies.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Docetaxel; Humans; Male; Meta-Analysis as Topic; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Salvage Therapy; Survival Rate; Taxoids

Topics: Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

A computer-assisted diagnostic system for analyzing bone scans (BONENAVI) calculates the automated bone scan index (aBSI). Here we evaluated the aBSI as a prognostic imaging biomarker for men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel.. We retrospectively analyzed 48 patients who received cabazitaxel for mCRPC and evaluated the ability of the aBSI to predict overall survival (OS). The Cox proportional hazards model was used to investigate the associations between baseline aBSI at cabazitaxel treatment and OS with the clinical variables as follows: age, number of cycles of docetaxel, serum prostate-specific antigen, hemoglobin (Hb), lactate dehydrogenase (LDH), and alkaline phosphatase. We determined the C-index to evaluate the discriminatory ability of our models when we included or excluded the aBSI from the analyses.. The median OS after cabazitaxel treatment was 10.0 months, and patients with aBSI ≤1% achieved significantly longer OS compared with patients with aBSI ≥1%. Multivariate analysis showed that age, Hb, LDH, and aBSI were independent prognostic factors of OS. Adding aBSI to the base model increased the C-index from 0.78 to 0.80.. The aBSI may serve as a useful imaging biomarker for predicting OS among men with mCRPC treated with cabazitaxel. Prospective studies are required to establish the value of aBSI as prognostic imaging biomarker.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers; Bone and Bones; Bone Density; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Taxoids; Whole Body Imaging

Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Taxanes chemotherapies represent the major therapeutic alternative for symptomatic mCRPC. While docetaxel is the most commonly prescribed Taxane for mCRPC; cabazitaxel has been approved for patients unresponsive to docetaxel. Still mCRPC remains incurable and patients often experience severe side effects. Recently, the FIRSTANA trial first demonstrated the absence of superiority in overall survival between cabazitaxel and docetaxel in mCRPC patients. Inversely, different toxicity were reported suggesting that cabazitaxel may provide a first line treatment option for some patients urging for a deeper characterization of cabazitaxel mechanisms of action as well as a re-evaluation of cabazitaxel conventional dose and schedule. In this study, our goal was therefore to evaluate the anti-tumor efficacy of various cabazitaxel regimens delivered as monotherapy or in combination with PEDF, a known anti-angiogenic and anti-neoplastic agent.. CRPC cells undergoing Taxane treatment were evaluated for cell proliferation, migration and death, and apoptosis using crystal violet staining, chemotaxis, cell cycle, and TUNEL assays. In vitro data were corroborated in CL1 CRPC xenografts where mice received intermittent or metronomic low-doses cabazitaxel ± PEDF.. We found that cabazitaxel inhibits the proliferation of CRPC cells with a higher efficacy than docetaxel in vitro. As expected, high-doses of Taxanes blocked the cells in mitosis. Surprisingly, low-doses of cabazitaxel induced more cell death than docetaxel mainly through apoptosis. In vivo, intermittent cabazitaxel lead to disease stabilization when combined with PEDF. Unexpectedly, low-doses of cabazitaxel delayed tumor growth with severe toxicity for some of the doses tested. Other results showed that PEDF and low-doses of cabazitaxel combination inhibited the migration of tumor cell and increased the tumoricidal activity of macrophages toward prostate tumor cells.. Our findings highlight the great promise of cabazitaxel drug and predict a possible move of cabazitaxel forward within the therapeutic sequence of prostate cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Death; Cell Line, Tumor; Cell Movement; Cell Proliferation; Docetaxel; Dose-Response Relationship, Drug; Eye Proteins; Humans; Macrophages; Male; Mice; Mice, SCID; Neoplasm Metastasis; Nerve Growth Factors; PC-3 Cells; Prostatic Neoplasms, Castration-Resistant; Recombinant Proteins; Serpins; Taxoids; Xenograft Model Antitumor Assays

Docetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.

Topics: Biomimetic Materials; Cell Line, Tumor; Cell Survival; Docetaxel; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Male; MicroRNAs; Prostatic Neoplasms, Castration-Resistant; Taxoids

Androgen deprivation therapy plus docetaxel (D-ADT) increases overall survival (OS) in men with high-volume, metastatic hormone-sensitive prostate cancer (mHSPC). Although the vast majority of men initially respond to D-ADT, most will progress and develop castration-resistant prostate cancer (CRPC). Little is known about the optimal treatment sequence for men with progressive disease on D-ADT.. Retrospective analysis of consecutive mHSPC patients treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison was undertaken. The primary end-points included radiographic progression free survival (rPFS) and OS with first-line treatment for metastatic CRPC (mCRPC).. Final analysis included 136 patients, median age 65 (range 35-86), 77% GS ≥ 8, and 79% with high-volume disease who received ≥3 cycles of docetaxel. Undetectable PSA values at 12 and 24 months were observed in 32% and 25% of patients, respectively. Median time to CRPC (biochemical, clinical, or radiographic) was 19.6 months (16.6-22.6). Sixty patients (44%) received ≥1 treatment for CRPC: 48 patients (80%) received a second-generation hormonal therapy (sHT). Among these, 22 received abiraterone acetate, 20 enzalutamide, and six a novel CYP-17 inhibitor on trial (ASN-001). Five patients (8%) received sipuleucel-T; four (7%) radium-223, five (8%) chemotherapy (two carboplatin-based, two single agent cabazitaxel, one single agent docetaxel) and three other. Patients receiving sHT as the first treatment for mCRPC had a median rPFS of 9.0 months (95%CI, 6.9-11.2) compared with 3.0 months (95%CI, 1.5-4.5) for patients who received a non-sHT (P = 0.024). The choice of first therapy for mCRPC was independent of GS (P = 0.909), visceral disease (P = 0.690) and time to CRPC (P = 0.844). Longer OS correlated with time to CRPC (P = 0.010) and first treatment for CRPC with sHT (P = 0.005).. For patients with progressive disease on D-ADT, subsequent treatment with a sHT is associated with a longer rPFS and OS.

Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Patient Selection; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

To date, there have not been any established biomarkers predicting the efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to evaluate the significance of the aspartate aminotransaminase (AST)/alanine aminotransaminase (ALT) ratio (De Ritis ratio) as a biomarker for mCRPC patients receiving cabazitaxel.. This study included 74 consecutive docetaxel-refractory mCRPC patients treated with cabazitaxel. It assessed the impact of the pretreatment De Ritis ratio, in addition to conventional clinicopathological parameters, on the oncological outcomes in these patients.. After treatment with cabazitaxel, 22 (29.7%) of the 74 patients achieved a prostate-specific antigen (PSA) response; however, there was no significant difference in the PSA response rate between patients with a low De Ritis ratio (<1.35) and those with a high ratio (≥1.35). In this series, the median periods of PSA progression-free survival (PFS) and overall survival (OS) after the introduction of cabazitaxel were 4.2 and 14.7 months, respectively. No significant difference was noted in PSA PFS between the low and high De Ritis ratio groups, whereas OS in the high De Ritis ratio group was significantly poorer compared with that in the low De Ritis ratio group. Univariate analysis showed the significant impact of the De Ritis ratio on OS, but not PFS, in these 74 patients. Furthermore, the De Ritis ratio, in addition to the performance status and lactate dehydrogenase level, was shown to be independently associated with OS on multivariate analysis.. Assessment of the De Ritis ratio may provide useful prognostic, but not predictive, information on cabazitaxel therapy in mCRPC patients.

Topics: Adenocarcinoma; Aged; Alanine Transaminase; Antineoplastic Agents; Aspartate Aminotransferases; Biomarkers, Tumor; Disease-Free Survival; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

The purpose of the study was to define clinical factors for successful treatment response and re-exposure to docetaxel in metastatic castration-resistant prostate cancer (mCRPC).. An mCRPC database of patients receiving first-line docetaxel and rechallenge courses was established. Several clinical factors were evaluated for prediction of treatment response. Multivariate cox-regression analysis was used to define pre-treatment and treatment factors for survival.. Between 2005 and 2013, 94 patients with mCRPC were treated with docetaxel. Full data set and follow-up were available for 62 patients. Median follow-up was 84 m [interquartile range (IQR) 64-104 m]. Median biochemical progression-free survival (bPFS) and overall survival under docetaxel were 9 m (IQR 5-16 m) and 20 m (IQR 16-26 m), respectively. Partial PSA-response at first docetaxel-sequence (n = 62), rechallenge (n = 32), and third-sequence (n = 22) docetaxel was 48.4%, 31.6%, and 34.8%, respectively. Time from start of primary androgen deprivation to CRPC > 47 m was the only independent pre-treatment parameter to predict improved overall survival (Hazard Ratio 0.48, p = 0.015). Interestingly, there was a strong trend for improved overall survival in patients with high Gleason Score (Hazard Ratio 0.58; p = 0.08). Partial PSA-response at docetaxel-rechallenge (Hazard Ratio 0.31; p = 0.008) and treatment-free interval > 3 m (Hazard Ratio 3.49; p = 0.014) were the only independent predictive factors under taxane treatment for overall survival.. Despite novel hormonal drugs, docetaxel still plays an important role in the treatment of mCRPC. Patients with partial-PSA-response at rechallenge or a treatment-free interval > 3 m benefit most from docetaxel re-exposure.

Topics: Aged; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Docetaxel; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Lymphatic Metastasis; Male; Middle Aged; Mitoxantrone; Neoplasm Grading; Orchiectomy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms, Castration-Resistant; Retreatment; Retrospective Studies; Survival Rate; Taxoids

This retrospective observational study assessed if second-line chemotherapy vs. androgen receptor-targeted agents (ARTAs; abiraterone/enzalutamide) is associated with improved outcomes in metastatic castration-resistant prostate cancer (mCRCaP) patients who experience early progression on first-line ARTAs in a US community setting.. Patients with mCRCaP (n = 345) who progressed ≤ 12 months after first-line ARTA and received second-line chemotherapy (docetaxel/cabazitaxel; n = 147) or ARTA (n = 198) between May 2011 and October 2014 were identified. Overall survival (OS), prostate-specific antigen (PSA) response and progression, and clinical response were compared for second-line chemotherapy vs. ARTA, using one-sided tests from second-line therapy initiation. Multivariate analyses were adjusted for: year, age, metastases, opioid use, Eastern Cooperative Oncology Group performance score, PSA, hemoglobin, alkaline phosphatase, lactate dehydrogenase (LDH), and albumin levels.. Patients receiving second-line chemotherapy vs. ARTA were younger (median: 74 vs. 79 years) and had a poorer prognosis in terms of PSA, LDH, alkaline phosphatase, albumin and hemoglobin levels, opioid use, and Halabi risk score (P < 0.05). Response rates were higher for chemotherapy vs. ARTA (PSA: adjusted odds ratio = 2.27, P = 0.005; clinical: adjusted odds ratio = 1.78; P = 0.020) and time to PSA progression was longer (adjusted hazard ratio [aHR] = 0.66; P = 0.010). A trend favored chemotherapy vs. ARTA for OS (aHR = 0.81, P = 0.148). Among patients with poor prognostic features, those receiving chemotherapy had significantly improved OS (Halabi intermediate-/high-risk score: aHR = 0.55, P = 0.009; hemoglobin < 11 g/dl: aHR = 0.41, P = 0.002; LDH > upper limit of normal: aHR = 0.18, P = 0.014; albumin < lower limit of normal: aHR = 0.42, P = 0.020).. Following early progression on first-line ARTA, second-line chemotherapy may be more beneficial in mCRCaP compared with second-line ARTA in patients with a poor prognosis.

Topics: Aged; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

The correlation of the oncological outcomes of docetaxel and cabazitaxel in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients has not been unclear.. This study included a total of 47 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the prognostic significance of cabazitaxel, focusing on patient age and the correlation of efficacy between docetaxel and cabazitaxel.. Prostate-specific antigen (PSA) decline was observed in 27 patients (57.4%), including 19 (40.0%) achieving the response defined by PSA decline ≥ 30%. The median overall survival (OS) periods after the introduction of cabazitaxel was 16.1 months. Twenty (42.6%) were judged to have responded to cabazitaxel with a PSA decrease ≥ 30% from the baseline. A 30% PSA response to cabazitaxel was achieved in 4 (50.0%) patients with ≧ 75 years (n = 8) and 16 (41.0%) patients with less than 75 years (n = 39). There was no significant correlation between the PSA response and patients' age (p = 0.707). A 30% PSA response to cabazitaxel was achieved in 13 (46.4%) and 7 (36.8%) patients with and without that to docetaxel, respectively. A 30% PSA response to cabazitaxel was achieved in 5 (16.6%) and 7 (41.2%) patients who had treated with less than 10 cycles docetaxel or 10 ≦ cycles, respectively. Univariate and multivariate analyses revealed that there were no significant correlation of patient age (p = 0.537), the response to prior docetaxel therapy (p = 0.339) or cycles of docetaxel therapy (p = 0.379) with shorter OS.. These results indicate that the introduction of cabazitaxel for Japanese mCRPC patients could result in oncological outcomes without any association with patient's age and the profiles of previous docetaxel therapy.

Topics: Adenocarcinoma; Age Factors; Aged; Antineoplastic Agents; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Prostate cancer is the second mortality cause among males with cancer. Patients with metastatic castration resistant prostate cancer (mCRPC) essentially die due to tumor progression in a castration resistance situation. Docetaxel based chemotherapy was the first therapeutic strategy that demonstrated a survival increase, in addition to pain decrease, increase in tumor responses and quality of life benefit, and it currently continues being useful after the incorporation of new therapies for the treatment of mCRPC. Cabazitaxel, a taxane with efficacy in docetaxel resistant tumors, was the second drug demonstrating increased survival in this scenario, and it is an additional alternative option effective in selected patients. Patients with aggressive variants and those with DNA repair genes alterations may benefit from platin-based therapies. In the absence of validated biomarkers, we should base our decisions on clinical and patient's preferences criteria. It is important to design a comprehensive therapeutic plan at an early stage including the treatments with demonstrated efficacy on survival. For this, it is essential a comprehensive and multidisciplinary evaluation of the patient at the start of therapy and during tumor evolution. This evaluation must be done with an adequate information process and shared decision together with the patient.

Topics: Antineoplastic Agents; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Cabazitaxel, which is a novel semi-synthetic anti-cancerous agent, is newly approved for the treatment of metastatic castration resistant prostate cancer(CRPC). The main dose-limiting toxicity is considered to be febrile neutropenia(FN). In this study, we retrospectively investigated the safety profiles of Japanese patients during cabazitaxel therapy. From September 2014 to August 2016, 17 patients initiated receiving cabazitaxel therapy in our institution. Prophylactically, pegfilgrastim was administered to all patients. Among 17 patients, 5 patients(29.4%)developed FN. Four of these patients(80%)developed FN in the first cycle and could continue the cabazitaxel therapy with dose modification, whereas 1 patient(20%)developed FN leading to septic shock in the 8th cycle. Although he recovered after appropriate medical treatment, he discontinued the cabazitaxel therapy. Regarding non-hematological adverse events, no unknown adverse events were observed. The most frequently observed adverse event was back pain(n=4, 23.5%). There was no influence on the continuation of treatment. Treatment discontinuation due to adverse events was observed in 1 patient(5.9%). Due to the prophylactic pegfilgrastim in combination, the occurrence rate of FN seemed to decrease. However, we must remember that FN is still frequently expressed even under the prophylactic pegfilgrastim.

Topics: Febrile Neutropenia; Filgrastim; Humans; Male; Polyethylene Glycols; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

With the approval of several new treatments for metastatic castration-resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen.. To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members.. A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan.. In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a hypothetical rate of 33%, the PMPM cost would decrease to $0.524, reflecting a cost saving of $0.004 PMPM and equating to incremental savings of $49,546, or $497 per patient per year (PPPY). In the second scenario, when out-of-pocket costs were not considered, the cost of second-line treatment after docetaxel was estimated as $6,733,594, or $0.561 PMPM. With a hypothetical increase in cabazitaxel use (24%-33%), the PMPM cost would decrease to $0.554, reflecting savings of $0.007 PMPM and equating to incremental savings of $86,136, or $864 PPPY. The primary driver of cost savings with increased cabazitaxel use was lower acquisition cost. One-way sensitivity analyses revealed that the model results were robust over a wide range of input values (utilization, prevalence, and population parameters).. In the presented BIM, an increase in cabazitaxel use is expected to result in modest cost savings to the health plan. Patient coinsurance savings may also be realized based on applicable Medicare Part B and Part D calculations. This BIM presents an objective, comprehensive, robust, and user-adaptable tool that health plans and medical decision makers may use to evaluate potential economic impact of formulary and reimbursement decisions.. Research and analysis were funded by Sanofi US. The sponsor had the opportunity to review the final draft; however, the authors were responsible for all content and editorial decisions. Flannery, Drea, Hudspeth, and Miao are employees of Sanofi. Miao is an owner of stock in Sanofi. Corman, Gao, and Xue are employees of Pharmerit International and served as consultants to Sanofi during this study. All authors contributed to study design and data collection and analysis. The manuscript was written by Flannery, along with the other authors, and revised by all the authors.

Topics: Antineoplastic Agents, Phytogenic; Budgets; Computer Simulation; Cost Savings; Docetaxel; Drug Costs; Drug-Related Side Effects and Adverse Reactions; Health Care Costs; Humans; Male; Managed Care Programs; Models, Economic; Prostatic Neoplasms, Castration-Resistant; Taxoids

We describe the case of a 55-year-old man who underwent four cycles of cabazitaxel therapy for castration-resistant prostate cancer (CRPC). After the fourth cycle of cabazitaxel, the patient experienced severe headaches. Brain gadolinium (Gd) contrast-enhanced magnetic resonance imaging (MRI) revealed multiple brain metastases. A few days later, the patient suffered impaired consciousness that progressed rapidly. The patient was treated for the symptoms of increased intracranial pressure and underwent whole-brain radiation. One month later, the patient's consciousness level and headache had improved. Although brain metastases of prostate cancer are rare, the possibility of brain metastases should be considered for prostate cancer patients, especially when a CRPC patient complains of headache. Additionally, even if major conditions such as cerebral hemorrhage are excluded by the use of non-contrast-enhanced computed tomography, brain Gd contrast-enhanced MRI should be performed in consideration of the possibility of brain metastases of prostate cancer.

Topics: Antineoplastic Agents; Brain Neoplasms; Contrast Media; Disease Progression; Gadolinium; Gamma Rays; Headache; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Taxoids

Cabazitaxel is approved for treatment of castration-resistant metastatic prostate cancer. The current dosing strategy of cabazitaxel is based on body surface area (BSA). Body surface area is known as a poor predictor for total systemic exposure to drugs, since it does not take into account variability in activity of metabolising enzymes, necessary for clearance of drugs. As exposure to cabazitaxel is related to treatment response, it is essential to develop a better individualised dosing strategy.. Ten patients with metastatic castration-resistant prostate cancer, who received cabazitaxel dosed on BSA as a part of routine palliative care, were enrolled in this study. Midazolam was administered as phenotyping probe for cytochrome P450 isoenzyme 3A (CYP3A). The relationship between midazolam and cabazitaxel clearance was investigated using non-linear mixed effects modelling.. The clearance of Midazolam highly correlated with cabazitaxel clearance (R=0.74). Midazolam clearance significantly (P<0.004) explained the majority (∼60%) of the inter-individual variability in cabazitaxel clearance in the studied population.. Metabolic phenotyping of CYP3A using midazolam is a promising strategy to individualise cabazitaxel dosing. Before clinical application, a randomised study is warranted.

Topics: Aged; Anti-Anxiety Agents; Antineoplastic Agents; Body Surface Area; Carcinoma; Cytochrome P-450 CYP3A; Humans; Male; Midazolam; Phenotype; Prostatic Neoplasms, Castration-Resistant; Taxoids

Topics: Abiraterone Acetate; Docetaxel; Humans; Male; Prednisone; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids

Docetaxel is one of the primary drugs used for treating castration resistant prostate cancer (CRPC). Unfortunately, over time patients invariably develop resistance to docetaxel therapy and their disease will continue to progress. The mechanisms by which resistance develops are still incompletely understood. This study seeks to determine the involvement of miRNAs, specifically miR-181a, in docetaxel resistance in CRPC.. Real-time PCR was used to measure miR-181a expression in parental and docetaxel resistant C4-2B and DU145 cells (TaxR and DU145-DTXR). miR-181a expression was modulated in parental or docetaxel resistant cells by transfecting them with miR-181a mimics or antisense, respectively. Following transfection, cell number was determined after 48 h with or without docetaxel. Cross resistance to cabazitaxel induced by miR-181a was also determined. Western blots were used to determine ABCB1 protein expression and rhodamine assays used to assess activity. Phospho-p53 expression was assessed by Western blot and apoptosis was measured by ELISA in C4-2B TaxR and PC3 cells with inhibited or overexpressed miR-181a expression with or without docetaxel.. miR-181a is significantly overexpressed in TaxR and DU145-DTXR cells compared to parental cells. Overexpression of miR-181a in parental cells confers docetaxel and cabazitaxel resistance and knockdown of miR-181a in TaxR cells re-sensitizes them to treatment with both docetaxel and cabazitaxel. miR-181a was not observed to impact ABCB1 expression or activity, a protein which was previously demonstrated to be highly involved in docetaxel resistance. Knockdown of miR-181a in TaxR cells induced phospho-p53 expression. Furthermore, miR-181a knockdown alone induced apoptosis in TaxR cells which could be further enhanced by the addition of DTX.. Overexpression of mir-181a in prostate cancer cells contributes to their resistance to docetaxel and cabazitaxel and inhibition of mir-181a expression can restore treatment response. This is due, in part, to modulation of p53 phosphorylation and apoptosis.

Topics: Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs; Pharmacogenetics; Prostate; Prostatic Neoplasms, Castration-Resistant; Taxoids

Cabazitaxel is a next generation taxane that has been shown to improve overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed during or after docetaxel-based therapy. A worldwide early access program (EAP) study was established to provide access to cabazitaxel ahead of commercial availability and to evaluate its safety and tolerability. The Australian EAP included patient-reported outcomes to evaluate the impact of cabazitaxel on quality of life (QoL). The final safety and QoL results from the Australian EAP for cabazitaxel are reported.. 104 patients from 18 Australian sites (median age at baseline, 70) enrolled in the EAP and completed at least one AQoL-8D questionnaire. Patients received a median of 6 cycles of cabazitaxel. 67 patients (64.4%) experienced grade ≥3 treatment-emergent adverse events (TEAEs); the most frequent TEAEs were neutropenia, febrile neutropenia, diarrhoea, and vomiting. QoL scores remained stable with increasing treatment cycles.. The results suggest that the safety profile cabazitaxel is manageable in the Australian clinical practice setting and that QoL is maintained with little or no detrimental effect of cabazitaxel in patients continuing on treatment without disease progression.

Topics: Aged; Australia; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids

It is unclear how treatment sequencing for metastatic castration-resistant prostate cancer (mCRPC) affects real-world patient outcomes. We assessed treatment sequences, patient characteristics and overall survival (OS) in post-docetaxel mCRPC patients. mCRPC patients receiving second-line cabazitaxel or androgen receptor-targeted therapy (ART; abiraterone/enzalutamide) post-docetaxel were identified using electronic medical records. OS was assessed from second-line therapy initiation using Cox regressions adjusting for: metastases; prostate-specific antigen (PSA); hemoglobin; alkaline phosphatase (ALP); albumin; second-line therapy initiation year. Following docetaxel (n = 629), 123 (19.6%) and 506 (80.4%) patients received cabazitaxel and ART, respectively. One hundred and ninety-five patients received additional treatments thereafter (54 following cabazitaxel; 141 following ART). Although patients receiving second-line cabazitaxel versus ART had similar disease characteristics at first-line therapy initiation, at second-line therapy initiation they had higher mean PSA (386.6 vs. 233.9 ng/mL) and ALP (182.0 vs. 167.3 u/L), lower mean hemoglobin (10.8 vs. 11.5 g/dL), and more frequently had intermediate/high-risk Halabi scores (61.8 vs. 48.4%); all p < 0.05. Overall, crude survival was not significantly different. Among Halabi high-risk patients, adjusted median OS was significantly longer in patients receiving cabazitaxel versus ART (HR 0.48; 95% CI 0.24-0.93; p = 0.030). Low albumin and hemoglobin led to similar findings (HR 0.43; 95% CI 0.23-0.80; p = 0.0077; HR 0.60; 95% CI 0.40-0.90; p = 0.014). Most post-docetaxel patients received second-line ART. Patients receiving second-line cabazitaxel had more high-risk features; however, second-line cabazitaxel administered after docetaxel may improve OS in patients with Halabi high-risk scores or low albumin/hemoglobin.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Longitudinal Studies; Male; Middle Aged; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Taxoids; Treatment Outcome

Topics: Biomarkers; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Metastatic castration-resistant prostate cancer that is progressing despite docetaxel chemotherapy is difficult to treat and often aggressive. If not previously used, modern androgen signaling inhibitors have established clinical activity in this setting. Cabazitaxel and radium-223 have also been shown to extend survival in appropriately selected patients. Carboplatin-containing chemotherapy regimens have not been studied in randomized trials with a survival endpoint, but they have demonstrated activity in phase II trials and are occasionally considered in the post-docetaxel setting. Recent identification of potentially exploitable targets in the molecular makeup of advanced prostate cancer has created opportunities for clinical trials of novel targeted agents, with poly(ADP-ribose) polymerase inhibitors yielding compelling early results in molecularly selected patients. Much remains to be done to improve the lot of patients with docetaxel-unresponsive metastatic castration-resistant prostate cancer.

Topics: Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

An elevated neutrophil-to-lymphocyte ratio (NLR) has been suggested to be associated with a poor prognosis in several cancers. We evaluated the utility of an elevated NLR as a biomarker to predict the prognosis of metastatic castration-resistant prostate cancer (mCRPC) patients treated with cabazitaxel (CBZ).. We analyzed 47 patients who received CBZ chemotherapy for mCRPC in our institutions. The NLR was calculated using the neutrophil and lymphocyte counts before CBZ chemotherapy. We determined the NLR cut-off value based on the sensitivity and specificity levels derived from area under the receiver operator characteristic curves for death. A multivariate analysis was performed to investigate the association between the NLR and the prognosis.. The median overall survival (OS) after CBZ was 10.0 months (range: 6.3-13.2). The median OS was shorter in patients with a high NLR (≥3.83) than in those with a low NLR (<3.83) (5.8 versus 13.2 months,. NLR might be a useful prognostic biomarker in mCRPC patients treated with CBZ.

Topics: Aged; Disease-Free Survival; Humans; Lymphocyte Count; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids

Effective treatment of metastatic castration resistant prostate cancer (mCRPC) remains an unmet challenge. Cabazitaxel (CBZ) is approved for mCRPC after docetaxel (DTX) failure, but the improvement in survival is only moderate (∼2 months) and patients suffer from significant side effects. Here, we report the development of a polymer based delivery system for CBZ to improve its safety and efficacy against DTX-resistant mCRPC. CBZ was conjugated to a carboxymethylcellulose-based polymer (Cellax-CBZ), which self-assembled into ∼100 nm particles in saline and exhibited sustained drug release in serum at 10%/day. Cellax-CBZ delivered 157-fold higher CBZ to PC3-RES prostate tumor in mice and could be safely administered at a 25-fold higher dose compared to free CBZ, resulting in superior tumor inhibition in multiple mice models of DTX-resistant CRPC. In a metastatic bone model of CRPC, Cellax-CBZ significantly improves overall survival with a 70% long-term survival rate to day 120, while mice treated with free CBZ had a median survival of 40 days. Cellax-CBZ induced mild and reversible neutropenia in mice but no other tissue damage. Cellax-CBZ showed significant potential for improving therapy of mCRPC over clinically approved CBZ.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Carboxymethylcellulose Sodium; Cell Line, Tumor; Delayed-Action Preparations; Docetaxel; Drug Carriers; Drug Compounding; Drug Liberation; Drug Resistance, Neoplasm; Humans; Male; Maximum Tolerated Dose; Mice, Inbred NOD; Mice, SCID; Nanoparticles; Neutropenia; Particle Size; Prostatic Neoplasms, Castration-Resistant; Solubility; Taxoids; Tissue Distribution; Xenograft Model Antitumor Assays

Our aim was to assess the efficacy and adverse effects of cabazitaxel (CBZ), a chemotherapeutic agent that can be administered to patients with metastatic castrate resistant prostate cancer (mCRPC) after docetaxel (DOC) therapy. We retrospectively analyzed data of CBZ received by mCRPC patients in 12 Hungarian oncological centers between 01/2016 and 06/2017. CBZ (25 or 20 mg/m2 q3w) was administered after DOC. Physical and laboratory examinations were performed in every cycle, tumor response was evaluated in every third cycle based on PCWG2 criteria. Adverse effects were evaluated based on CTCAE 4.0. Data of 60 patients were analyzed. CBZ was administered in 2nd and 3rd lines in 31.6% and 46.6%, while in 4th and 5th lines in 15% and 6.6% patients, respectively. Its starting dose was 25 mg/m2 and 20 mg/m2 in 65% and 35% of cases, respectively. The median number of cycles was 5. Progression-free survival and overall survival were 5.52 and 15.77 months, respectively. Survival results were similar in case of DOC-CBZ-ART/alfaradin and DOC-ART/alfaradin-CBZ sequences. Adverse effects were detected in 63,3% of patients. The most common adverse effects were neutropenia, anemia, and diarrhea. Our observations suggest that CBZ, with the appropriate support and chemotherapeutic experience, is well-tolerated and effective therapy of mCRPC after DOC.. A kabazitaxel (KBZ) az áttétes, kasztrációrezisztens prosztatarákos (mCRPC) betegeknél docetaxel (DOC) után alkalmazható kemoterapeutikum, mely javítja a túlélést is. Célunk a kezelés hatékonyságának és biztonságosságának értékelése volt. 2016. 01. hó és 2017. 06. hó között hazánk 12 onkológiai központjában mCRPC miatt KBZ-vel kezelt betegek retrospektív adatelemzését végeztük. Az induló dózis 25 vagy 20 mg/m2 volt, 3 hetente. Ciklusonként fizikális és laborvizsgálat, 3 ciklusonként képalkotó és PSA-vizsgálattal PCWG2 szerint tumorválasz-meghatározás történt. A mellékhatásokat CTCAE 4.0 szerint értékeltük. Hatvan beteg adatait elemeztük. KBZ 2. és 3. vonalban 31,6, ill. 46,6%-ban, míg 4. és 5. vonalban 15, ill. 6,6%-ban történt. A kezdõ dózis 25 mg/m2 volt 65%-ban, 20 mg/m2 35%-ban. Medián ciklusszám 5. A progressziómentes túlélés 6,47, a teljes túlélés 15,77 hónap. A túlélés azonos volt a DOC-KBZ-ART/alfaradin, illetve DOC-ART/alfaradin-KBZ szekvenciákban. Mellékhatást 63,3%-ban észleltünk, leggyakrabban neutropéniát, anémiát és hasmenést. Tapasztalataink alapján a KBZ megfelelõ szupportációval és kemoterápiás jártassággal alkalmazva jól tolerálható és hatékony terápia mCRPC DOC-kezelése után. A nemkívánatos események elõfordulása megegyezett az irodalmi adatokkal.

Topics: Age Factors; Aged; Biopsy, Needle; Cohort Studies; Disease-Free Survival; Docetaxel; Humans; Hungary; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Patient Safety; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome

Topics: Androgen Antagonists; Androstenes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials, Phase III as Topic; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

To examine health-related quality of life (QoL) in men with metastatic castration-resistant prostate cancer (mCRPC) on cabazitaxel.. Men with mCRPC receiving cabazitaxel (25 mg/m², every 3 weeks) and 10 mg/day oral prednis(ol)one were enrolled (2011-2014) in the non-interventional prospective 'QoLiTime' study. Primary outcome was change in QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item) with respect to prostate-specific antigen (PSA) response after four cycles of cabazitaxel. Secondary outcomes included occurrence of adverse events (AEs).. Of 527 men, 348 received four cycles of cabazitaxel and 266 had the necessary PSA level measurements. After four cycles, 92 (34.6%) men had a PSA level decrease ≥50% (responders). QoL remained stable throughout the study (P = 0.62). Change in QoL did not differ between responders and non-responders (P = 0.69). Change in PSA level and global health status between baseline and four cycles showed an inversely proportional relationship (correlation coefficient -0.14; 95% confidence interval -0.26 to -0.01; P = 0.03), with increasing PSA level corresponding to lower health status. Responders showed no change in physical functioning vs baseline (-1.75, P = 0.12); non-responders showed a reduction vs baseline (-7.00, P < 0.001) and responders (P = 0.05). Responders showed an improvement in pain vs baseline (-7.61, P = 0.05) and vs non-responders (P = 0.01). AEs occurred in 292 patients (55.4%), most commonly anaemia (16.5%), fatigue (12.3%) and diarrhoea (11.8%). Neutropenia and febrile neutropenia were reported in 3.8% and 3.6% of patients, respectively.. Prostate-specific antigen level response was associated with stable physical functioning and improvement in pain. Symptom increases were seen in areas typical of chemotoxicity, but QoL was maintained.

Topics: Adult; Aged; Aged, 80 and over; Humans; Male; Middle Aged; Pain; Pain Management; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids

The present study aims to evaluate the efficacy of cabazitaxel in combination with prednisone treatment in Italian patients affected by hormone-refractory metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel plus prednisone.. Thirty patients with mCRPC were enrolled between June 2013 and January 2016 (the last follow-up was in January 2016). Cabazitaxel was used according to the summary of product characteristics and administered at a dose of 25 mg/m2 every 3 weeks plus oral prednisone at a dose of 5-mg tablets twice a day continuously. The reduction in serum prostate-specific antigen (PSA) was the primary endpoint while reducing pain, safety, progression-free survival, response rate and overall survival (OS) were secondary endpoints.. Cabazitaxel was well tolerated, showing a manageable toxicity profile, associated with a modest objective response rate and a good reduction in PSA levels. Only 12 patients (40%) had a partial response, 10 patients (33%) showed stabilization of disease and 8 (27%) experienced disease progression. The median OS was 14.8 months (95% CI: 11.6-19.8). The linear regression analysis revealed that PSA response was an important predictor of OS, showing a positive correlation with OS (β = 0.377, p < 0.01).. Three-week treatment with cabazitaxel was found to be valid and was a well-tolerated treatment option for patients with mCRPC after a first-line docetaxel treatment.

Topics: Aged; Antineoplastic Agents; Disease Progression; Docetaxel; Humans; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Taxoids

Although myeloid growth factors are commonly used to treat metastatic castration-resistant prostate cancer (mCRPC), the optimal timing of administration has not been well studied. We assessed the effects of same-day pegfilgrastim, a neutrophil stimulator, after cabazitaxel treatment with or without carboplatin in patients with mCRPC. We also evaluated the frequency of urinary tract inflammation during treatment.. Between September 2010 and September 2014, 151 consecutive patients with mCRPC underwent cabazitaxel treatment with or without the addition of carboplatin at a single institution. We assessed absolute neutrophil count recovery, incidence of neutropenia, neutropenic fever, antibiotic usage, treatment delays or discontinuation, dose reduction, and hospitalization with pegfilgrastim administration. Radiologists blinded to therapy reviewed computed tomography scans to detect urinary tract inflammation.. The median patient age was 69 years (range, 41-88 years); 78% of patients were white, and 54% had a Gleason score ≥ 9. Median overall survival was 9 months (95% confidence interval, 8-11 months). One patient (< 1%) had neutropenia; 38 patients (25%) had infection. During cycle 1, a significantly higher proportion of patients receiving pegfilgrastim after 24 hours developed infection than did those receiving pegfilgrastim the same day (26% vs. 6%; P = .01).. Same-day pegfilgrastim administration after cabazitaxel treatment with or without carboplatin in patients with mCRPC is feasible. The urinary tract inflammation rate (21%) was higher than that reported anecdotally. Results need to be prospectively validated.

Topics: Adult; Aged; Aged, 80 and over; Carboplatin; Disease-Free Survival; Drug Administration Schedule; Filgrastim; Humans; Incidence; Male; Middle Aged; Neoplasm Grading; Neutropenia; Polyethylene Glycols; Prostatic Neoplasms, Castration-Resistant; Taxoids; Urinary Tract Infections

Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen-responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer.

Topics: Androgen Antagonists; Animals; Disease Models, Animal; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Male; Mice; Mice, Nude; Mice, Transgenic; Prostatic Neoplasms, Castration-Resistant; Taxoids

Until 2014, docetaxel chemotherapy had been performed as a castration resistant prostate cancer (CRPC) treatment and continued as long as possible because we had no other option except docetaxel. Recently, several new agents including abiraterone, enzalutamide and cabazitaxel are available for CRPC patients. Although we have several treatment options, they are not curative and most of CRPC patients ultimately develop resistance. Furthermore, because AR targeted agents have cross-resistance each other, the taxane chemotherapy that is expected to have less cross-resistance to AR targeted agents may play an important role in the case of AR targeted agent failure. It is crucial about when to start chemotherapy or to switch from docetaxel to cabazitaxel.

Topics: Antinematodal Agents; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Recurrence; Taxoids

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.. Intratumoral concentrations of docetaxel and cabazitaxel were correlated with antitumor activity in docetaxel-naïve, docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer.. Intratumoral drug levels were negatively related to intrinsic and acquired resistance to docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs.. The superior antitumor activity of cabazitaxel in docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to docetaxel resulting from suboptimal intratumoral docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927-936, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Antineoplastic Agents; Benzamides; Docetaxel; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Xenograft Model Antitumor Assays

Prostate cancer is among the most common cancers in males. Prostate cancer is androgen dependent in the beginning, but as time progresses, it becomes refractory to androgen deprivation treatment. At this stage, docetaxel has been used as standard treatment for years. Cabazitaxel has become the first chemotherapeutic agent which has been shown to increase survival for patients with metastatic Castrate Resistant Prostate Cancer (mCRPC) that progresses after docetaxel. Phase 3 TROPIC study demonstrated that cabazitaxel prolongs survival.. In this study, we evaluated a total of 103 patients who took cabazitaxel chemotherapy for mCRPC diagnosis in 21 centers of Turkey, retrospectively. This study included patients who progressed despite docetaxel treatments, had ECOG performance score between 0-2, and used cabazitaxel treatment. Patients received cabazitaxel 25 mg/m2 at every 3 weeks, and prednisolone 5 mg twice a day.. Median number of cabazitaxel cures was 5.03 (range: 1-17). Cabazitaxel response evaluation detected that 34% of the patients had a partial response, 22.3% had stable disease and 32% had a progressive disease. Grade 3-4 hematological toxicities were neutropenia (28.2%), neutropenic fever (14.5%), anemia (6.7%), and thrombocytopenia (3.8%). In our study, median progression-free survival (PFS) was 7.7 months and overall survival (OS) was 10.6 months.. This study reflects toxicity profile of Turkish patients as a Caucasian race. We suggest that cabazitaxel is a safe and effective treatment option for mCRPC patients who progress after docetaxel. Moreover, ethnicity may play important roles both in treatment response and in toxicity profile.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome; Turkey

To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel (CA) as second-line or third-line therapy in the everyday clinical setting. Charts from 94 patients treated with CA as second-line (n=28) or third-line therapy (n=66) were evaluated. Common Terminology Criteria for Adverse Events were used to register grade 3-4 nonhematological toxicity during treatment with CA. Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen (PSA) percentage change were registered during treatment with CA and previous/subsequent novel androgen receptor targeting therapies. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A median of 6 versus 5 treatment cycles was administered in patients treated with second-line and third-line CA (P=0.483). Events with grade 3-4 nonhematological toxicity were equally distributed in the two groups (32 vs. 35%, P=0.80). PSA responses were observed in 46 and 17% of patients treated with second-line and third-line CA (P=0.002). PFS (5.5 vs. 3.3 months, P=0.087, log rank) and OS (18.3 vs. 11.4 months, P=0.003, log rank) was longer in patients treated with second-line CA. OS measured from second-line abiraterone acetate/enzalutamide was similar (18.0 months) to second-line CA (P=0.883, log rank). Treatment-related toxicity was independent of CA being administered as second-line or third-line therapy. Although PFS and the frequency of PSA responders favored patients treated with second-line CA, one treatment sequence could not be considered superior to the other in this study.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Docetaxel; Humans; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Taxoids

Topics: Clinical Trials as Topic; Humans; Male; Prognosis; Prostatic Neoplasms, Castration-Resistant; Taxoids

To evaluate the efficacy of enzalutamide (Enz) as fourth- or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients.. We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz.. All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7).. Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes.

Topics: Abdominal Neoplasms; Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Bone Neoplasms; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Lymphatic Metastasis; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Retreatment; Retrospective Studies; Survival Rate; Taxoids

Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Clinical Trials as Topic; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Cabazitaxel, abiraterone acetate (AA), and enzalutamide have been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel chemotherapy. Whether taxanes and next-generation androgen receptor (AR) axis inhibitors are cross-resistant or not is a subject of debate.. To evaluate the antitumour activity of cabazitaxel in mCRPC pretreated with abiraterone or enzalutamide.. The antitumour activity of cabazitaxel was assessed in patients with mCRPC and progressive disease after treatment with docetaxel and AA. In parallel, cabazitaxel antitumour activity was studied in enzalutamide-resistant models.. Changes in prostate-specific antigen (PSA) levels and progression-free survival were used to determine the activity of cabazitaxel treatment. Cell proliferation, immunofluorescence, and AR transactivation assay were used in enzalutamide-resistant models.. A total of 79 patients who had progressive mCRPC after docetaxel (median: 8 cycles; range: 4-12 mo), and AA (median: 4.8 mo; range:1-55 mo) received cabazitaxel 25mg/m(2) every 3 weeks (median: 6 cycles; range:1-15 cycles). A PSA decline ≥30% was achieved in 48 patients (62%; 95% confidence interval [CI], 51-73), and a decline ≥50% was achieved in 28 patients (35%; 95% CI, 25-47). The median progression-free survival and overall survival were 4.4 and 10.9 mo, respectively. In vitro, cabazitaxel decreased cell viability in both enzalutamide-sensitive and enzalutamide-resistant prostate cancer cells within the same range of concentrations. PC3, an AR-negative cell line, exhibited similar sensitivity to cabazitaxel.. Cabazitaxel and AR-pathway inhibitors are not cross-resistant. Preclinical data suggest that cabazitaxel activity does not act mainly through AR axis inhibition.. The antitumour activity of cabazitaxel, a chemotherapy agent, was studied in prostate cancer resistant to conventional hormonal therapy and to more recent endocrine therapies (abiraterone or enzalutamide). Cabazitaxel retained anticancer activity in more than half of the cases.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease-Free Survival; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; France; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Signal Transduction; Taxoids; Time Factors; Treatment Outcome

Topics: Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids

Cabazitaxel and abiraterone have both received approval for treating metastatic castrate-resistant prostate cancer (mCRPC) patients after first-line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel-treated mCRPC patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mCRPC patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December 2012. Primary outcome measure was overall survival (OS); secondary measures were progression-free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty-three and 69 patients received Cab→Abi (cabazitaxel prior to abiraterone) and Abi→Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab→Abi and Abi→Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab→Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mCRPC patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher-line therapy in the selected study population.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

We report the case of a 51-year-old patient with metastatic prostate cancer at diagnosis and primary refractoriness to both androgen ablation therapy and docetaxel. At the time of cabazitaxel initiation, the patient had only osseous metastases and was constrained to a wheelchair because of bone pain. Ten cycles of cabazitaxel were administered, and a remarkable response was achieved, with improvement in biochemical markers, performance status, and bone scan findings. Two months after suspension of treatment by choice, the patient developed jaundice because of massive hepatic metastases and died after a few days because of hepatic failure.

Topics: Humans; Liver Neoplasms; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Taxoids

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that can stabilize some proteins by inhibiting degradation mediated by protein phosphatase 2A (PP2A), and its level in cancer is associated with resistance to chemotherapy. However, whether CIP2A could increase chemoresistance of prostate cancer (PCa) cells to chemotherapeutic agent cabazitaxel remains unclear. To determine whether CIP2A serves as a potential therapeutic target of human PCa, we utilized small interference RNA (siRNA) to knock down CIP2A expression in human PCa cells and analyzed their phenotypic changes. The data demonstrated that CIP2A was significantly elevated in mCRPC cell lines C4-2 and ARCaP(M) at both the mRNA and protein levels. CIP2A silencing led to decreased proliferation and enhanced chemosensitivity and apoptosis to cabazitaxel in human PCa cells, as well as reduced Akt phosphorylation. Our data suggesting critical roles of CIP2A in PCa cells chemoresistance to cabazitaxel and raising the possibility of CIP2A inhibition as a promising approach for chemosensitization of metastatic castration-resistant prostate cancer (mCRPC).

Topics: Antineoplastic Agents; Apoptosis; Autoantigens; Cell Line, Tumor; Cell Proliferation; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Phosphorylation; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; Taxoids

The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit.. To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA.. We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel.. The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis.. We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences.. We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy.. It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent.

Topics: Abiraterone Acetate; Aged; Antineoplastic Agents; Benzamides; Cohort Studies; Disease-Free Survival; Docetaxel; Humans; Italy; Male; Multivariate Analysis; Nitriles; Phenylthiohydantoin; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Failure; Treatment Outcome

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.. We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.

Topics: Aged; Animals; Antineoplastic Agents; Benzamides; Disease Models, Animal; Disease Progression; Docetaxel; Drug Resistance, Neoplasm; Humans; Ki-67 Antigen; Male; Mice; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Treatment Outcome

To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.. Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro and in xenograft tumors for cabazitaxel response.. The data herein show that (i) cabazitaxel exerts stronger cytostatic and cytotoxic response compared with docetaxel, especially in CRPC; (ii) cabazitaxel induces aberrant mitosis, leading to pyknotic and multinucleated cells; (iii) taxanes do not act through the androgen receptor (AR); (iv) gene-expression profiling reveals distinct molecular actions for cabazitaxel; and (v) tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to cabazitaxel.. Cabazitaxel not only induces improved cytostatic and cytotoxic effects, but also affects distinct molecular pathways, compared with docetaxel, which could underlie its efficacy after docetaxel treatment has failed in patients with CRPC. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization to taxanes, which could benefit up to 50% of CRPC cases.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Flow Cytometry; Humans; Immunoblotting; Male; Mice; Microscopy, Fluorescence; Models, Molecular; Oligonucleotide Array Sequence Analysis; Prostatic Neoplasms, Castration-Resistant; Taxoids; Transcriptome; Xenograft Model Antitumor Assays

Optimal sequencing of cabazitaxel (C) and abiraterone acetate (A) after docetaxel (D) for metastatic castration-resistant prostate cancer (mCRPC) is unclear. We assessed treatment patterns and outcomes in patients with mCRPC receiving different sequences of A or C, or both, after administration of D.. Retrospective analysis was conducted of US Oncology Network iKnowMed (iKM) electronic health record (EHR) data to assess patients with mCRPC who received treatment with D and were subsequently treated with C or A, or both, between April 2011 and May 2012. Patients received 2 or 3 drugs: DA, DC, DAC, or DCA. Overall survival (OS) and time to treatment failure (TTF) were analyzed by the Kaplan-Meier method from the start to the end of second-line therapy after administration of D (TTF1) and to the end of combined second- and third-line therapy (TTF2) for 3-drug sequences. Multivariable Cox proportional hazard models evaluated the impact of baseline clinical prognostic factors and treatment sequence on OS and TTF.. Of 350 patients who were treated with D and subsequent therapies, 183 (52.3%) received DA, 54 (15.4%) received DC, 77 (22.0%) received DCA, and 36 (10.3%) received DAC. In a multivariable analysis, adjusted comparisons suggested that 3-drug sequences were associated with improved OS versus 2-drug sequences (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.092-0.476; P = .0002). There were no statistically significant differences in OS and TTF for DC versus DA, and OS was significantly greater for DCA versus DAC (HR, 0.13; 95% CI, 0.022-0.733; P = .0210). More cycles of C were administered in DCA than in DAC (median 6 vs. 4; t test P < .0001), whereas the duration of A treatment was similar.. Administration of 3 agents in the DCA sequence was more optimal for treating mCRPC in this hypothesis-generating study.

Topics: Abiraterone Acetate; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Cabazitaxel is a second line chemotherapy drug recently approved for the treatment of metastatic castration-resistant prostate cancer. A first panel of French experts and a second independent panel of European experts were convened to assess the conformity of prescription of cabazitaxel with a Delphi consensus method. A two-round modified Delphi consensus process was conducted. This methodology is based on experts' opinion obtained in a systematic manner. The process was divided into five steps: (i) elaboration of the questionnaire, (ii) rating, (iii) analysis, (iv) discussion of the points with absence of consensus following rating of the questionnaire, and (v) final reporting. Consensus was defined according to RAND method and all analyses were conducted according to the same methodology. At the end of the two rounds of rating and a synthesis meeting, of the 26 items included in the Summary of Product Characteristics (SPC), 11 items were judged appropriate with strong consensus by the two independent panels of experts. These items can therefore be considered of prime importance to evaluate conformity of cabazitaxel prescription in the context of observatory studies as well as in further clinical trials using this new taxane. Our findings further provide important evidence about the value of the Delphi consensus and highlight a requirement for "conformity" standards to assist practitioners in a safe chemotherapy drug prescription.

Topics: Antineoplastic Agents; Drug Prescriptions; France; Humans; Male; Practice Patterns, Physicians'; Prostatic Neoplasms, Castration-Resistant; Surveys and Questionnaires; Taxoids

Docetaxel is used as the first-line chemotherapy for castration-resistant prostate cancer (CRPC), but docetaxel resistance occurs in part owing to induction of P-glycoprotein (P-gp) encoded by multidrug resistance protein 1 (MDR1) gene. A recently developed taxane-cabazitaxel-has poor affinity for P-gp and is thereby effective in docetaxel-resistant CRPC. It has been recently demonstrated that exosomes in the body fluids could serve as a diagnostic marker because they contain proteins and RNAs specific to the cells from which they are derived. In this study, we aimed to investigate if P-gp in blood exosomes could be a marker to diagnose docetaxel resistance and select a taxoid for patients with CRPC.. Exosomes were isolated by differential centrifugation from docetaxel-resistant prostate cancer (PC-3) cells (PC-3R) and their parental PC-3 cells and from the serum of patients. Silencing of P-gp was performed by small interfering RNA transfection. Protein expression was examined by Western blot analysis. Viability of cells treated with docetaxel or cabazitaxel was determined by water soluble tetrazolium salt (WST) assay.. The level of P-gp was higher in exosomes as well as cell lysates from PC-3R cells than in those from PC-3 cells. Cabazitaxel effectively killed PC-3R cells, and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel. The P-gp level in blood exosomes was relatively higher in clinically docetaxel-resistant patients than in therapy-naïve patients.. Our results suggest that detection of P-gp in blood exosomes, which is involved in resistance to docetaxel but not to cabazitaxel, could be useful to diagnose docetaxel resistance and select an appropriate taxoid for patients with CRPC-docetaxel or cabazitaxel.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Survival; Docetaxel; Drug Resistance, Neoplasm; Exosomes; Humans; Male; Prostatic Neoplasms, Castration-Resistant; RNA, Small Interfering; Taxoids; Transfection

Topics: Antineoplastic Agents; Biomarkers, Tumor; Bone Neoplasms; Caenorhabditis elegans Proteins; Health Status Indicators; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Taxoids; Ubiquitin-Conjugating Enzymes

Both abiraterone acetate (AA) and cabazitaxel (Cbz) have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel (D). Although no standard sequencing has been established as yet, Cbz has recently been proven to be active after AA. However, to date, few data are available on its safety in this setting. Therefore, the primary endpoint of this study was to investigate Cbz tolerability in mCRPC patients treated previously with D and AA. From April 2011 to the present, 43 mCRPC patients received AA after D at our institution. Of these, 22 patients were subsequently treated with Cbz and were evaluable for toxicity in the present retrospective study. Cbz was administered at a dose of 25 mg/m plus 10 mg oral prednisone every 3 weeks. Adverse events (AEs) were reported using the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. Despite the advanced stage of disease and frailty of our study population, there were no unexpected side effects. The most common AEs were hematologic. Neutropenia was observed in nine (40.9%) patients and of grade≥3 in six (27.2%). No febrile neutropenia occurred. The most common nonhematologic AEs were diarrhea and asthenia, reported in eight (36.3%) and in five (22.7%) patients, respectively. In this setting, Cbz toxicity seems to be manageable and comparable with second-line Cbz. Therefore, our results seem to support the safety of Cbz as a third-line treatment for mCRPC patients.

Topics: Aged; Androstenes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Endpoint Determination; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Failure

We previously showed that pretreatment detection of androgen receptor splice variant-7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer is associated with resistance to abiraterone and enzalutamide, but not to taxane chemotherapies. Here, we conducted serial measurements of AR-V7 and evaluated patterns of longitudinal AR-V7 dynamics over the course of multiple sequential therapies.. Metastatic prostate cancer patients treated at Johns Hopkins with AR-directed therapies or taxane chemotherapies underwent serial liquid biopsies for CTC-based AR-V7 analysis at baseline, during therapy, and at progression. We used a CTC enrichment platform followed by multiplexed reverse-transcription polymerase chain reaction analysis to detect full-length androgen receptor and AR-V7 transcripts. Patients selected for inclusion in this report were those who provided ≥4 CTC samples, at least one of which was AR-V7 positive, over the course of ≥2 consecutive therapies.. We identified 14 patients who received a total of 37 therapies and contributed 70 CTC samples for AR-V7 analysis during a median follow-up period of 11 months. Three patients remained AR-V7 positive during the entire course of therapy. The remainder underwent transitions in AR-V7 status: there were eight instances of 'conversions' from AR-V7-negative to -positive status (during treatment with first-line androgen deprivation therapy, abiraterone, enzalutamide, and docetaxel), and six instances of 'reversions' from AR-V7-positive to -negative status (during treatment with docetaxel and cabazitaxel).. AR-V7 is a dynamic marker, and transitions in AR-V7 status may reflect selective pressures on the tumor exerted by therapeutic interventions. While 'conversions' to AR-V7-positive status were observed with both AR-directed therapies and taxane chemotherapies, 'reversions' to AR-V7-negative status only occurred during taxane therapies. Serial blood-based AR-V7 testing is feasible in routine clinical practice, and may provide insights into temporal changes in tumor evolution.

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Docetaxel; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Nitriles; Phenylthiohydantoin; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Reverse Transcriptase Polymerase Chain Reaction; Taxoids; Treatment Outcome

Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory. A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells. Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy.

Topics: Active Transport, Cell Nucleus; Alternative Splicing; Animals; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Cytoplasm; Docetaxel; Drug Resistance, Neoplasm; Fluorescence Recovery After Photobleaching; Gene Deletion; Gene Expression Regulation, Neoplastic; Humans; Ligands; Male; Microtubules; Prostatic Neoplasms, Castration-Resistant; Protein Structure, Tertiary; Receptors, Androgen; Signal Transduction; Taxoids; Transcription, Genetic; Up-Regulation

We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown.. To investigate whether AR-V7-positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men.. We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men.. We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone).. Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7-positive and AR-V7-negative men (41% vs 65%; P = .19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7-positive and AR-V7-negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7-positive men, whereas outcomes did not differ by treatment type in AR-V7-negative men. In AR-V7-positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003).. Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7-positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7-negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell-based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

Topics: Academic Medical Centers; Adenocarcinoma; Aged; Aged, 80 and over; Androstenes; Antineoplastic Agents; Baltimore; Benzamides; Biomarkers, Tumor; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Genetic Predisposition to Disease; Humans; Kallikreins; Kaplan-Meier Estimate; Male; Middle Aged; Neoplastic Cells, Circulating; Nitriles; Patient Selection; Phenotype; Phenylthiohydantoin; Predictive Value of Tests; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Risk Factors; RNA, Messenger; Taxoids; Time Factors; Treatment Outcome

Topics: Cystitis; Hemorrhage; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

Topics: Androstenes; Androstenols; Benzamides; Bridged-Ring Compounds; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the management of advanced castrate-resistant prostate cancer.. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Society of Medical Oncology (2013), the American Urological Association (2013), the National Institute of Health and Clinical Excellence (2014) and the American Society of Clinical Oncology and Cancer Care Ontario (2014). Recommendations on the management of advanced castrate-resistant prostate cancer were developed.. These adapted guidelines form the SCAN Guidelines 2015 for the management of advanced castrate-resistant prostate cancer.

Topics: Adenocarcinoma; Androgen Antagonists; Androstenes; Antineoplastic Agents; Benzamides; Cancer Vaccines; Docetaxel; Gonadotropin-Releasing Hormone; Humans; Ketoconazole; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radium; Singapore; Taxoids; Tissue Extracts

To evaluate the cost-effectiveness of abiraterone, cabazitaxel, and enzalutamide compared to placebo for treatment of metastatic castration-resistant prostate cancer.. A decision-tree model compared three treatment options for metastatic castration-resistant prostate cancer patients over 18 months from a societal perspective in 2012 USD. Chance nodes included baseline pain as a severity indicator, significant adverse effects (neutropenia, cardiac events, or seizures), and survival. Probabilities, survival rates, and health utilities were from clinical trials (COU-AA, TROPIC, and AFFIRM) and other published studies. Survival of enzalutamide was adjusted to match placebo groups across trials. Probabilistic sensitivity analyses, acceptability curves and net benefit calculations were performed.. Abiraterone was the most cost-effective of the treatments ($123.4 K/quality-adjusted life year) compared to placebo, enzalutamide was $437.6 K/quality-adjusted life year compared to abiraterone, and cabazitaxel was $351.9 K/quality-adjusted life year compared to enzalutamide. Enzalutamide and cabazitaxel were not cost-effective compared to placebo at $154.3 K/quality-adjusted life year and $163.2 K/quality-adjusted life year, respectively. Acceptability curves showed abiraterone was cost-effective 29.3% of the time with a willingness to pay threshold of $100 K. The model was sensitive to changes in cost of the drugs, life expectancy, and survival rate. Sensitivity analysis shows that enzalutamide can become the most cost-effective option if the price of the medication decreased by 26% and other drug costs remained the same.. Based on the cost-effective analysis, and survival adjustments necessary to match placebo groups, we would recommend abiraterone for treatment of metastatic castration-resistant prostate cancer despite not quite falling under the usually accepted willingness to pay threshold. Further analysis should examine comparative survival across the three drugs.

Topics: Androstenes; Antineoplastic Agents; Benzamides; Cost-Benefit Analysis; Decision Trees; Drug Costs; Financing, Personal; Humans; Male; Models, Economic; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Quality-Adjusted Life Years; Survival Rate; Taxoids

The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy setting.. Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test, Mann-Whitney U test and linear regression model were used to test for differences in PSA response.. All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was -12% (range -56% to 76%), while the median best PSA response was -22% (-76% to 76%). Forty-six percent had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate with the number of prior cancer treatments (p = 0.57), time from diagnosis to mCRPC (p = 0.11) or prior response to docetaxel (p = 0.67). However, patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The median OS was 4.8 months.. Previous abiraterone therapy is associated with a less marked fall in PSA following enzalutamide therapy in post-chemotherapy mCRPC patients compared with reported results in randomized trials. Larger prospective studies of sequencing are warranted.

Topics: Abiraterone Acetate; Aged; Androstadienes; Antineoplastic Agents; Benzamides; Cohort Studies; Compassionate Use Trials; Disease-Free Survival; Docetaxel; Humans; Kallikreins; Linear Models; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Failure; Treatment Outcome

Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians.. To describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents.. We report on a cohort of 59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of whom had received prior enzalutamide.. Changes in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy.. The post-endocrine-therapy patients received abiraterone (n=32), sequential abiraterone and enzalutamide (n=5) or enzalutamide (n=4). These patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median of six cabazitaxel cycles (range: 1-10 cycles) were delivered, with ≥ 50% PSA declines in 16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naïve cohort (n=18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis.. This is the first report of cabazitaxel activity in CRPC progressing after treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant cabazitaxel activity in this setting.. We looked at the antitumour activity of the chemotherapy drug cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after these novel endocrine treatments.

Topics: Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease Progression; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retreatment; Retrospective Studies; Survival Rate; Taxoids; Treatment Failure

Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access programmes (EAPs) were established worldwide, allowing access to cabazitaxel before its commercial availability. Preliminary results of the European CUP/EAP, focusing on the elderly population (aged > or =70 years), are reported.. Enrolled patients with progressive mCRPC received cabazitaxel (25 mg/m2) plus 10mg oral prednisone/prednisolone every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. Safety was analysed by age group (<70, 70-74 and > or =75 years). The influence of selected variables on grade > or =3 neutropenia and/or neutropenic complications was analysed in multivariate analysis.. 746 men were enrolled (<70 years, n=421; 70-74, n=180, > or =75 years, n=145). Number of cabazitaxel cycles, dose reductions for any cause, dose delays possibly related to cabazitaxel adverse events, and tolerability were similar in the three age groups. Prophylactic granulocyte colony-stimulating factor (G-CSF) use was more common in men aged > or =0 years. In multivariate analysis, age > or =75 years, treatment cycle 1, and neutrophil count <4000/mm3 before cabazitaxel injection were associated with increased risk of developing grade > or =3 neutropenia and/or neutropenic complications. Prophylactic use of G-CSF at a given cycle significantly reduced this risk by 30% (odds ratio 0.70, p=0.04).. The results suggest that cabazitaxel has a manageable safety profile in everyday clinical practice. Prophylactic use of G-CSF, especially at cycle 1 and in men aged > or =75 years, is important and improves tolerability in senior adults treated with cabazitaxel.

Topics: Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Compassionate Use Trials; Diarrhea; Disease Progression; Drug Administration Schedule; Europe; Humans; Male; Middle Aged; Multivariate Analysis; Nausea; Neoplasm Metastasis; Neutropenia; Prednisolone; Prednisone; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

A prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival.. Multicentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan-Meier method and compared using the log-rank test.. Overall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾ 50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾ 30% rather than ⩾ 5 0% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾ 50% or ⩾ 30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS).. The PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Epidemiologic Methods; Humans; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Cabazitaxel, a next-generation taxane, retains its efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress on new androgen receptor (AR)-targeted agents such as abiraterone acetate or enzalutamide. These findings are reinforced by in vitro preclinical data confirming cross-resistance between abiraterone and enzalutamide, but not between cabazitaxel and AR-targeted agents.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Evidence-Based Medicine; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC.. One hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods.. Twenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69).. A limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids

Prostate cancer is a heterogeneous disease that responds variably to available agents, particularly androgen receptor(AR)- targeting agents. In preclinical models, cabazitaxel, a second-generation taxane, demonstrated enhanced antitumor activity when compared with docetaxel. In subsequent clinical trials, cabazitaxel was associated with pharmacokinetic, safety, and tolerability profiles consistent with those of previous taxanes. In the pivotal phase III study(TROPIC; NCT00417079), cabazitaxel led to significantly improved overall survival in patients with metastatic castration-resistant prostate cancer(mCRPC), compared with mitoxantrone, when both were administered in combination with prednisone/prednisolone(median survival: 15.1 months[95%confidence interval(CI): 14.1-16.3]vs 12.7 months[95% CI: 11.6-13.7], hazard ratio(HR): 0.70[95% CI: 0.59-0.83], p<0.0001), and it also extended progression-free survival. Furthermore, a long-term analysis of the TROPIC trial revealed that the survival benefit with cabazitaxel was maintained at 2 years, with 60(15.9%)patients in the cabazitaxel group and 31(8.2%)patients in the mitoxantrone group surviving for B2 years(odds ratio: 2.11, 95% CI: 1.33-3.33). Cabazitaxel also provides pain palliation similar to that provided by using mitoxantrone. The safety profile of cabazitaxel is consistent with that of first-generation taxanes, and gastrointestinal(predominantly diarrhea)and hematologic(mainly neutropenia)adverse events are the most frequently reported. Clinical trial data suggest that these events can be managed with careful monitoring and dose reduction where necessary. In addition, treatment with granulocyte colony-stimulating factor(G-CSF)can mitigate hematologic adverse events, whereas supportive treatment with antiemetic and antidiarrheal agents may ameliorate gastrointestinal symptoms. The treatment paradigm for mCRPC is evolving rapidly with the emergence of data for new agents, leading to maximization of patient benefits. The proven efficacy and tolerability profiles of cabazitaxel suggest the promising role of this agent within this paradigm.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Humans; Japan; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Taxoids

To report the efficacy and safety of using cabazitaxel plus prednisolone chemotherapy to treat Korean patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel therapy.. This cohort study enrolled 26 mCRPC patients. Treatment consisted of 25 mg/m(2) cabazitaxel that was intravenously administered every 3 weeks, in addition to twice-daily 5 mg prednisolone.. The median patient age was 67 years (range = 53-82), median Eastern Cooperative Oncology Group performance status was 1 (range = 0-2), Gleason score was ≥ 8 in 25 patients (96 %), and median serum prostate-specific antigen (PSA) was 95.3 ng/mL (interquartile range = 9.1-297.7). A total of 180 treatment cycles were administered, and a median of five cycles were administered per patient (range = 1-23). A PSA response was observed in 32 % of evaluable patients. Tumor response was evaluated in eight patients, and three and four patients achieved partial response and stable disease, respectively. Over a median follow-up duration of 23.4 months (95 % CI 11.1-35.6), median time to treatment failure was 4.2 months (95 % CI 1.8-6.6) and median time to progression was 8.5 months (95 % CI 3.0-13.1). Median overall survival was 16.5 months (95 % CI 12.1-20.9). Grade 3 or worse febrile neutropenia developed in eight patients (31 %) and neutropenic infection in four patients (15 %).. Cabazitaxel plus prednisolone chemotherapy can be used to treat Korean mCRPC patients. Prophylactic growth factor support should be considered for patients at high risk of neutropenic fever or infection.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Asian People; Cohort Studies; Compassionate Use Trials; Diarrhea; Drug Administration Schedule; Fatigue; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neutropenia; Prednisolone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Republic of Korea; Taxoids; Treatment Outcome

Taxanes are the only chemotherapies used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study, we show that ERG overexpression in in vitro and in vivo models of CRPC is associated with decreased sensitivity to taxanes. ERG affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of docetaxel or cabazitaxel with tubulin. Finally, analysis of a cohort of 34 men with metastatic CRPC treated with docetaxel chemotherapy reveals that ERG-overexpressing prostate cancers have twice the chance of docetaxel resistance than ERG-negative cancers. Our data suggest that ERG plays a role beyond regulating gene expression and functions outside the nucleus to cooperate with tubulin towards taxane insensitivity. Determining ERG rearrangement status may aid in patient selection for docetaxel or cabazitaxel therapy and/or influence co-targeting approaches.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cohort Studies; Docetaxel; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids; Trans-Activators; Transcriptional Regulator ERG; Tubulin

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Taxoids

We report the case of an 80-year-old patient who presented with a progressive prostate metastatic cancer with poor performance status. The patient had already benefitted from docetaxel and abiraterone. A new line of chemotherapy by cabazitaxel was started with good response, and there was a dramatic improvement in general status and pain symptoms. Age and performance status alone should not be limiting decision factors for elderly cancer patients.

Topics: Age Factors; Aged, 80 and over; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Until 2010, chemotherapy with docetaxel was the only approved agent for treatment of metastatic castrate resistant prostate cancer (mCRPC). Since then, the therapeutic landscape of mCRPC has changed rapidly. Multiple novel agents have received regulatory approval after demonstrating improved overall survival in separate randomized Phase 3 studies. These include immunotherapeutic agent sipuleucel-T, androgen axis inhibitors abiraterone and enzalutamide, and a novel microtubule inhibitor cabazitaxel. More recently, radium-223, a bone-targeting alpha emitting radiopharmaceutical, was reported to improve skeletal related events, as well as overall survival in a Phase 3 randomized study. Additionally, there are several promising agents in the advanced stages of clinical development. Here, we describe the agents recently shown to improve overall survival, and those that have reached the advanced stages of development in Phase 3 clinical trials. We will also propose a strategy for optimal sequencing of these agents in the treatment of mCRPC.

Topics: Androstenes; Androstenols; Anilides; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Humans; Imidazoles; Ipilimumab; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Quinolines; Quinolones; Radioisotopes; Radium; Taxoids; Thionucleotides; Tissue Extracts

Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of the Dutch CUP, detailing the safety and efficacy of cabazitaxel in a routine clinical practice setting.. Safety and efficacy data of all 5 Dutch centers participating in the cabazitaxel CUP were collected. Safety data were collected prospectively using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Overall survival (OS) and progression-free survival (PFS), time to PSA progression (TTPP), and best clinical response were evaluated retrospectively.. Fifty-one patients were registered in the CUP; 49 received cabazitaxel. Forty-two of 49 patients [85.7%], 42 patients had ≥ 2 metastatic sites. Patients received on average 6 cabazitaxel cycles (range, 1-21). A dose reduction or dose delay occurred in 13 and 20 patients [26.5% and 40.9%] respectively. Prophylactic granulocyte colony-stimulating factor (G-CSF) was used in 8 patients [16.3%]. Grade ≥ 3 adverse events were observed in 25 patients [51.0%]; 16 patients [32.7%] discontinued treatment because of treatment-emergent adverse events (TEAEs). Serious adverse events (SAEs) occurred in 16 (32.7%) patients; the most frequent SAEs were hematuria (4 patients [8.3%]) and urosepsis (3 patients [6.3%]). Febrile neutropenia occurred twice; no patient had grade ≥ 3 neuropathy. No toxicity-related mortality occurred. Median follow-up was 24.1 months. Median OS was 8.7 months (interquartile range [IQR], 6.0-15.9 months); median TTPP was 2.8 months (IQR, 1.7-5.9 months).. In the Dutch CUP, patients with advanced mCRPC had delayed tumor progression with acceptable toxicities using cabazitaxel treatment.

Topics: Aged; Compassionate Use Trials; Disease-Free Survival; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Neoplasm Metastasis; Netherlands; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival; Taxoids; Treatment Outcome

Prostate cancer is the most common noncutaneous cancer among men. This case report describes a 43-year-old man with rapidly progressing castration-resistant prostate cancer (CRPC) that responded initially to docetaxel and did not tolerate cabazitaxel. He subsequently received a third line of chemotherapy with cyclophosphamide and prednisone, and experienced a dramatic clinical and radiographic response in his liver metastases. This therapeutic intervention led to a significant clinical benefit and confirms the potential use of cyclophosphamide in patients with CRPC, particularly those with liver metastases.

Topics: Adult; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Cyclophosphamide; Docetaxel; Humans; Male; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

Treatment 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.. To 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.. We 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.. In 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.

Topics: Active Transport, Cell Nucleus; Androstenes; Androstenols; Benzamides; Blotting, Western; Cell Line, Tumor; Cell Nucleus; Cell Survival; Docetaxel; Dose-Response Relationship, Drug; Drug Interactions; Drug Resistance, Neoplasm; Green Fluorescent Proteins; Humans; Male; Microscopy, Confocal; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids; Time-Lapse Imaging