cabazitaxel and Prostatic-Neoplasms

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

Prostate cancer (PC) is a major health issue in developed countries, with, on the one hand, men suffering from sequelae related to unnecessary treatment of non-lethal PC, and, on the other hand, still dying because of advanced PC that progresses to castration-resistant disease. Systemic treatment is the mainstay of therapy of castration-resistant PC (CRPC). To date, a multitude of systemic agents have been tested and many of these have failed to provide a clinically meaningful benefit in CRPC, while others have been approved by the US Food and Drug Administration and/or the European Medicines Agency, including antiandrogen hormonal drugs (abiraterone, enzalutamide, apalutamide), chemotherapy (docetaxel and cabazitaxel), immunotherapy (Sipuleucel-T), and radiopharmaceutical (Radium-223) agents. In this review, systemic treatments regarded as most likely to have an impact in clinical practice are presented and discussed. In addition to the pivotal clinical studies, selected retrospective and non-randomized clinical trials are also discussed if deemed to have an impact on clinical practice or future research. A comprehensive appraisal of the expanding landscape of systemic therapies for advanced PC is provided from an expert perspective, with a focus on novel classification and diagnostic tools that have been paving the way for the development of precision medicine in PC.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Clinical Trials as Topic; Docetaxel; Humans; Immunotherapy; Male; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Radiopharmaceuticals; Radium; Retrospective Studies; Taxoids; Thiohydantoins; Tissue Extracts

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

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

Prostate cancer is the most common cancer among American men and the second most common cause of cancer deaths among men. Treatment of prostate cancer remains a challenge. Despite decades of research, few cytotoxic chemotherapy agents have shown promise against prostate cancer. In this paper, we will discuss the history of chemotherapy in prostate cancer, the pivotal trials with docetaxel that advanced the field, the cytotoxic chemotherapy agents, including cabazitaxel, as well as combination therapy with docetaxel or cabazitaxel and the potential implications of biomarkers such as AR-V7 in chemotherapy use.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Docetaxel; Humans; Male; Neoplasm Metastasis; Prostate; Prostatic Neoplasms; Taxoids

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

There has been dramatic improvement in the diagnosis and treatment of prostate cancer recently. The treatment of localized disease became more successful with the application of new, sophisticated techniques available for urologic surgeons and radiotherapists. Nevertheless a significant proportion of patients relapses after the initial local treatment or is diagnosed with metastatic disease at the beginning. In the past five years, six new drugs became registered for the treatment of metastatic, castration-resistant prostate cancer, such as sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, the α-emitting radionuclide alpharadin and the receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor denosumab. The availability of these new treatment options raises numerous questions. In this review we present the standard of care of metastatic prostate cancer by disease stage (hormone naive/ hormone sensitive metastatic prostate cancer, non-metastatic castration-resistant prostate cancer, oligometastatic/multimetastatic castration-resistant prostate cancer) and the emerging treatment modalities presently assessed in clinical trials. We would also like to give advice on debatable aspects of the management of metastatic prostate cancer.. A prosztatadaganat kezelésében az utóbbi évtized jelentõs fejlõdést eredményezett, javultak a daganat felismerésének lehetõségei azáltal, hogy pontosabb diagnosztikai módszerek állnak rendelkezésre. A nem metasztatikus daganat gyógyítási esélyei is javultak a fejlõdõ sugárterápia és az egyre hatékonyabb sebészi megoldások következtében. Ennek ellenére jelentõs azon betegek száma, akiknél a lokális ellátás ellenére progresszió alakul ki, vagy már a diagnózis felállításakor metasztatikus a betegség. A kasztrációrezisztens prosztatarák kezelésében az elmúlt öt év során 6 új hatóanyag került törzskönyvezésre. Ezek közül kettõ az androgén tengelyt célzó kezelések közé tartozik, a többi hatóanyag, illetve terápiás eljárás: immunterápia, kemoterápia, izotópkezelés és a RANK-ligand gátlása. Az új kezelések kapcsán számos kérdés merül fel. Közleményünk célja elõrehaladott prosztatadaganatban stádiumok (hormonnaiv/hormonérzékeny metasztatikus, kasztrációrezisztens nem metasztatikus, kasztrációrezisztens oligo- és multimetasztatikus) szerint a már egyértelmû evidenciák ismertetése, az új fejlesztések bemutatása, nyitott kérdések megvitatása.

Topics: Adrenal Cortex Hormones; Androgen Antagonists; Androstenes; Antineoplastic Agents, Hormonal; Benzamides; Bone Neoplasms; Denosumab; Drug Administration Schedule; Drug Approval; Gonadotropin-Releasing Hormone; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Tissue Extracts

Until recently, docetaxel-based chemotherapy was the only established treatment for patients with metastatic hormone refractory prostate cancer (mHRPC). In 2010 to 2011, 3 more agents were shown to be associated with a survival benefit in mHRPC, including the dendritic cell vaccine sipuleucel-T, the 17,20 lyase inhibitor abiraterone, and the taxane cabazitaxel. The improved understanding of prostate cancer biology in recent years led to the development of drugs directed against precise tumorigenesis-associated molecular pathways. Molecular pathways involved in the progression of mHRPC include the androgen receptor, angiogenesis, endothelin receptor, tyrosine kinases (SRC, MET, vascular endothelial growth factor receptor, RET), and the receptor activator of nuclear factor-kB-ligand. This review will focus on recent advances in the standard treatments paradigm, and promising new targeted agents that are being investigated, in mHRPC.

Topics: Androgen Antagonists; Androstenes; Androstenols; Angiogenesis Inhibitors; Antineoplastic Agents; Cancer Vaccines; Cathepsin K; Dendritic Cells; Docetaxel; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Radiopharmaceuticals; RANK Ligand; Receptors, Endothelin; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; src-Family Kinases; Taxoids; Tissue Extracts

Prior to 2010, the treatment options for castrate-resistant prostate cancer (CRPC) were limited. In the past 3 years, four new agents have been approved by the US Food and Drug Administration for use in CRPC. These four agents differ in their mechanisms of action and highlight the progress made in our understanding of CRPC, and more importantly, provide options with proven clinical benefit. This review examines the development, investigational evolution, adverse events, and future direction of: 1) the androgen receptor inhibitor, enzalutamide, 2) androgen biosynthesis inhibitor, abiraterone, 3) novel taxane chemotherapy, cabazitaxel, and 4) autologous immunotherapeutic agent, sipuleucel-T.

Topics: Androgen Antagonists; Androstenes; Androstenols; Benzamides; Cancer Vaccines; Combined Modality Therapy; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids; Tissue Extracts; United States

The taxane derivative cabazitaxel (Jevtana(®)) is approved in the USA and the EU for use in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. In the pivotal TROPIC trial, overall survival was significantly prolonged with cabazitaxel plus prednisone versus mitoxantrone plus prednisone in patients with metastatic castration-resistant prostate cancer who had progressed during or after docetaxel therapy. In addition, progression-free survival, the times to tumour progression and prostate specific antigen (PSA) progression, and tumour and PSA response rates were improved with cabazitaxel plus prednisone. Intravenous cabazitaxel had an acceptable tolerability profile, with haematological adverse events occurring most commonly, and diarrhoea being the most common nonhaematological adverse event.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Disease-Free Survival; Europe; Humans; Male; Neoplasm Metastasis; Neutropenia; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome; United States

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Denosumab; Docetaxel; Humans; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Taxoids

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of cabazitaxel (Jevtana®, sanofi-aventis, UK) to submit evidence of its clinical and cost effectiveness for the second-line treatment of metastatic hormone-refractory prostate cancer (mHRPC). The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer's submission to NICE. Clinical evidence was derived from a multinational randomized open-label phase III trial of cabazitaxel plus prednisone or prednisolone in men with mHRPC that had progressed during or following treatment with docetaxel. The comparator was mitoxantrone plus prednisone or prednisolone. Use of cabazitaxel was associated with a statistically significant improvement in overall survival, median progression-free survival and time to tumour progression. However, it was also associated with an increased incidence of adverse events such as neutropenia. Utility data were based on interim results from the early access programme for cabazitaxel. Data were only available for a small number of patients with stable disease, resulting in great uncertainty as to the effect of cabazitaxel on quality of life. For their economic evaluation, the manufacturer estimated that the use of cabazitaxel was associated with an incremental cost of £74,908 per QALY gained. However, the ERG disagreed with the manufacturer over two key methodological points. The first concerned modelling and extrapolating survival; the second point was concerned with the choice of patient population. The ERG altered the manufacturer's evaluation to take into account these two points of disagreement. The resulting cost per QALY gained was £82,950. The NICE Appraisal Committee believed the analysis presented by the ERG to be more plausible, and likely to be an underestimate of the cost per QALY. They concluded that whilst the clinical effectiveness of cabazitaxel had been proven, it was not likely to represent a cost-effective use of NHS resources and so its use could not be recommended.

Topics: Antineoplastic Agents; Cost-Benefit Analysis; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; United Kingdom

Published efficacy and safety data from clinical trials of three recently approved agents for the management of metastatic castration-resistant prostate cancer (CRPC) are reviewed.. Sipuleucel-T is approved by the Food and Drug Administration (FDA) for the treatment of asymptomatic or minimally symptomatic patients with CRPC. In a placebo-controlled Phase III clinical trial, the use of sipuleucel-T was associated with an average improvement in median overall survival of 4.1 months. Abiraterone acetate and cabazitaxel are approved by FDA as second-line treatments for patients with CRPC who experience disease progression during first-line docetaxel therapy. In Phase III trials, abiraterone acetate was associated with improved overall survival relative to placebo use (14.8 months versus 10.9 months), and cabazitaxel was found to confer an overall survival advantage over mitoxantrone therapy (median survival, 15.1 months versus 12.7 months), corresponding to a 30% reduction in the relative risk of death (hazard ratio, 0.7; 95% confidence interval, 0.59-0.83; p < 0.0001). The three agents range in cost from $40,000 to $93,000 for a full course of therapy. Sipuleucel therapy entails leukapheresis procedures for the collection of autologous cells used in dose preparation, requiring careful planning and coordination of care.. Sipuleucel-T, abiraterone acetate, and cabazitaxel offer new options for the treatment of patients with CRPC, including those with disease resistant to standard first-line therapies. The agents' varying administration requirements, as well as patient-specific factors and cost issues, are key considerations in the drug selection process.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Cancer Vaccines; Clinical Trials as Topic; Fees, Pharmaceutical; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts

Several effective drugs have become available for prostate cancer therapy, which are being used after the development of castration resistance and studied already at an earlier stage of prostate cancer therapy. Novel hormonally acting drugs include degarelix, enzalutamide and abiraterone. Cytotoxic agents that have proven effective in studies include the docetaxel derivative cabazitaxel, denosumab in the prevention of complications caused by bone metastases, and radium-233 chloride as treatment for bone metastases. The optimal sequence of administration of the novel drugs as well as combining them are subject to intensive research.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Denosumab; Gonadotropin-Releasing Hormone; Humans; Male; Nitriles; Oligopeptides; Phenylthiohydantoin; Prostatic Neoplasms; Radioisotopes; Radium; Taxoids

Over the past few years, we have developed an increased understanding of the molecular mechanisms that underlie prostate cancer progression and castration resistance and expanded our repertoire of therapeutic options for castration-resistant prostate cancer (CRPC). Four new agents (cabazitaxel, abiraterone acetate, enzalutamide, and radium-233) have been shown to prolong overall survival in patients with CRPC in the postchemotherapy setting. Targeting the androgen receptor pathway continues to have an important role in the treatment of CRPC, with abiraterone acetate and enzalutamide being the most exciting developments. Cabazitaxel is now considered the standard-of-care second-line chemotherapy for men with metastatic CRPC (mCRPC). Bone-targeted therapy is an active area of research, with denosumab being the first bone-targeted agent able to significantly delay the appearance of bone metastases in patients with CRPC and radium-223 being the first radiopharmaceutical agent to improve survival in patients with mCRPC.

Topics: Androgen Antagonists; Benzamides; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Treatment Outcome

Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal, Humanized; Benzamides; Castration; Clinical Trials as Topic; Denosumab; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Tissue Extracts

To describe drugs used in the non-hormonal treatment of metastatic prostate cancer.. Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned.. The metabolic radiotherapy although under-used for this indication, kept a place at the beginning of the disease. Radium-223 chloride seems to have to occupy an important place in the coming years. The chemotherapy, the only recourse until very recently in the castration-resistant prostate cancer, must redefine its place partially. The denosumab provide an interesting alternative to bisphosphonates.. The non-hormonal treatment of the metastatic disease of the prostate cancer is changing rapidly with the emergence of new molecules. Urologist must know perfectly these new drugs.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Density Conservation Agents; Cisplatin; Denosumab; Docetaxel; Etoposide; Humans; Male; Mitoxantrone; Organometallic Compounds; Organophosphorus Compounds; Osteoporosis; Prostatic Neoplasms; Radiation Protection; Radioisotopes; Radium; RANK Ligand; Strontium; Strontium Radioisotopes; Taxoids

Castration-resistant prostate cancer (CRPC) has historically presented significant challenges to both clinicians and patients in regard to disease progression and consequent management. The first advances in the treatment of this state of prostate cancer with docetaxel chemotherapy demonstrated a survival benefit over the palliative standard of care, mitoxantrone combined with prednisone. The recognition that these patients still maintained active androgen receptor access identified new therapeutic agents for CRPC that aimed to further deplete testosterone levels or directly interact with the androgen receptor (ie, enzalutamide). Other therapeutic targets that have established efficacy in randomized phase 3 trials include bone metastases (ie, radium 223 dichloride), the immune system (ie, sipuleucel-T), and tubulin (ie, cabazitaxel). These new and evolving agents are positioned to substantially alter the therapeutic environment for CRPC and to improve patient outcomes and quality of life.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Middle Aged; Mitoxantrone; Neoplasm Invasiveness; Neoplasm Staging; Prednisone; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Treatment Outcome

Cabazitaxel has recently been approved by FDA for the treatment of docetaxel resistant hormone-refractory prostate cancer. It has been developed by Sanofi-Aventis under the trade name of Jevtana. It is given in combination with prednisone/prednisolone and has passed the clinical trial over well-known drug mitoxantrone. This drug is a microtubule depolymerization inhibitor, which can penetrate blood brain barrier (BBB). The FDA granted fast track designation to this drug in November 2009 and thereafter, new drug application submission was done in March 2010. Priority review to this drug was granted in April 2010 and finally in July 2010 it was approved by FDA. It is available in the form of injection in the dose of 60 mg/1.5 mL, which should be diluted prior to its use by the diluents supplied along with the injection. It is a second-line drug and has proven to be effective in patients experiencing docetaxel based treatment failure.

Topics: Animals; Antineoplastic Agents; Docetaxel; Drug Approval; Drug Resistance, Neoplasm; Humans; Male; Prostate; Prostatic Neoplasms; Taxoids; Tubulin Modulators

Recently, licensed and emerging treatments for metastatic castrate-resistant prostate cancer are transforming the prognosis for men whose disease has already progressed during or after docetaxel-based chemotherapy. Two agents (cabazitaxel and abiraterone) are already accessible to prescribers, having shown survival benefits versus their comparators in randomized controlled trials, and other agents are showing promising results. A future in which metastatic castrate-resistant prostate cancer can be managed as a 'chronic disease' looks tantalizingly close. The challenge for clinicians will be to use these treatments rationally, in a way that optimizes each individual patient's chances of prolonged survival.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Docetaxel; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prognosis; Prostatic Neoplasms; Survival Rate; Taxoids

Recently, new agents have been developed in the treatment of prostate cancer. Our aim was to review phase III studies that involved novel agents in the treatment of castration resistant prostate cancer.. PubMed databases were searched for original articles published with the search terms: prostate cancer, castration resistant, metastatic, targeted therapy, biologic agents, immunotherapy and clinical trials. Proceedings from 2008 of conferences of the American Society of Clinical Oncology, American Urological Association, and the European Association of Urology were also searched. We included phase III studies that involved: abiraterone, MDV 3100, cabazitaxel, sipuleucel-T, radium-223, and denosumab.. Abiraterone and MDV 3100 are two new hormotherapies that showed an increased overall survival of 15 and 18 months respectively before after docetaxel based chemotherapy in randomized trials. Cabazitaxel became the standard second line chemotherapy after docetaxel. Sipuleucel-T has emerged as the first approved vaccine in prostate cancer. It showed a 22 % reduction of mortality and a prolonged survival time of 4.1 months compared to placebo. A radium-223 based metabolic radiotherapy has showed a better overall survival, delayed and reduced skeletal-related events in placebo controlled randomized trials. Denosumab also delayed the first skeletal-related event in a zoledronic acid controlled trial (20.7 versus 17.1 months, P=0.0002). Moreover, Denosumab delays bone metastases by 4.1 months compared to placebo.. The novel agents that emerged in the treatment of prostate cancer showed an efficacy in placebo controlled trials. They added new tools in the armamentarium of therapies of castration resistant prostate cancer.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Denosumab; Disease-Free Survival; France; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Radioisotopes; Radium; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Tissue Extracts; Treatment Outcome

Every year in Germany approximately 12,000 men die of castration-resistant prostate cancer even though early detection using PSA-based diagnostics allows more patients to be diagnosed with a curable cancer. An established first line therapy at this stadium is docetaxel chemotherapy, given in a 3-week regimen, providing an overall survival advantage of 2 months. In 6-9 months, the patients treated primarily with docetaxel will progress to a docetaxel-insensitive phase which requires a secondary systemic therapy. Increasing understanding of molecular signal transduction has permitted a growing variety of promising modern drugs, including cabazitaxel, sipuleucel-T and abiraterone. More prospective clinical data will provide a large variety of different therapy combinations, sequence therapies or other therapy regimens particularly for selected subgroups of patients with castration-resistant prostate cancer.

Topics: Androstenes; Androstenols; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Clinical Trials as Topic; Combined Modality Therapy; Docetaxel; Humans; Male; Mitoxantrone; Neoplasm Recurrence, Local; Orchiectomy; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Survival Rate; Taxoids; Tissue Extracts

Improved understanding of mechanisms underlying metastatic castration-resistant prostate cancer (mCRPC) progression has led to the recognition of multiple molecular targets and advances in the therapeutic landscape. The addition of abiraterone acetate, sipuleucel-T, cabazitaxel, and denosumab to the therapeutic armamentarium and the impending addition of MDV-3100 and radium-223 underscore the importance of androgen pathway inhibition, immunotherapy, tubulin antagonism, and pathophysiology of bone metastasis.. Review the next generation of molecular targets in mCRPC.. Medline databases were searched for >100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy. Proceedings from the last 5 yr of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched. We included novel and promising drugs that have reached clinical trial evaluation.. The major findings were addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.. mCRPC is a disease with multiple molecular drivers. Molecular pathways being targeted in ongoing phase 3 trials are androgen signaling (MDV3100, TAK700), immunoregulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod). The strides made in identifying multiple other novel molecular targets offer potential opportunities for further improving outcomes.

Topics: Abiraterone Acetate; Androstadienes; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bone Neoplasms; Cancer Vaccines; Carcinoma; Clinical Trials, Phase III as Topic; Clusterin; Dasatinib; Denosumab; Humans; Ipilimumab; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Pyridines; Pyrimidines; Quinolines; Quinolones; Radium; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Taxoids; Thiazoles; Tissue Extracts; Treatment Outcome; Vaccines, Synthetic

The purpose of this review article is to present the current treatment options for castrate resistant prostate cancer in addition to the recently approved agents and their role in treatment.. The biology of prostate cancer and the data supporting the use of traditional chemotherapeutic options in castrate resistant prostate cancer are reviewed. The newly approved agents, sipuleucel-T, cabazitaxel, and abiraterone, are presented as well. The studies that led to the approval of these three agents are discussed in this article as well as their current and potential roles in the treatment of castrate resistant prostate cancer.. New mechanisms, drugs, and clinically relevant molecular targets show survival advantage and are new options available for patients after traditional chemotherapy. The roles of these new agents have yet to be further clarified in future studies.

Topics: Androstenes; Androstenols; Animals; Antineoplastic Agents; Drug Approval; Humans; Male; Molecular Targeted Therapy; Orchiectomy; Prostatic Neoplasms; Survival Rate; Taxoids; Tissue Extracts; United States; United States Food and Drug Administration

The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Three new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer patients: sipuleucel-T (Provenge), cabazitaxel (Jevtana), and abiraterone acetate (Zytiga). Additionally, there are several other promising prostate cancer agents in late-stage development, including MDV3100, PROSTVAC-VF (Prostvac), orteronel (TAK-700), and radium-223 chloride (Alpharadin), each with a novel mechanism of action. Taken together, we have entered a period of accelerated drug development and optimism in the care of advanced prostate cancer. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents.

Topics: Abiraterone Acetate; Androstadienes; Humans; Male; Prostatic Neoplasms; Taxoids; Tissue Extracts; Treatment Outcome

On March 17, 2011 the European Commission issued a marketing authorization valid throughout the European Union for Jevtana® (Sanofi-Aventis, Paris, France) for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. The active substance of Jevtana® is cabazitaxel acetone solvate, an antineoplastic agent that acts by disrupting the microtubular network in cells. The recommended dose of cabazitaxel is 25 mg/m2 administered as a 1-hour i.v. infusion every 3 weeks in combination with oral prednisone or prednisolone, 10 mg, administered daily throughout treatment. In the main study submitted for this application, a 2.4-month longer median overall survival time and a 30% lower risk for death were observed for cabazitaxel, compared with mitoxantrone. The most common side effects with cabazitaxel were anemia, leukopenia, neutropenia, thrombocytopenia, and diarrhea. This paper summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency Web site (http://www.ema.europa.eu).

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Drug Approval; Drug-Related Side Effects and Adverse Reactions; European Union; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Rate; Taxoids; Treatment Outcome

Abiraterone acetate and cabazitaxel have shown an overall survival benefit in patients with metastatic castration-resistant prostate cancer following docetaxel failure. Both have been approved in this indication. The search, follow-up and characterisation of circulating tumor cells should help for the response evaluation and the choice between the two treatments. Recently, alpharadin (radium-223 chloride) has demonstrated also an overall survival advantage in a large phase III trial. Other hormone therapies as MDV3100 or TAK700 are very promising. In undifferentiated cancers with neuroendocrine features, etoposide and platinum salts combinations have shown low efficiency.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Angiogenesis Inhibitors; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms; Radioisotopes; Radium; Taxoids; Treatment Failure

If androgen deprivation, chemical with LH-RH analogs or surgical with bilateral orchiectomy, still remains the stone edge of treatment of prostate cancer, in the metastatic setting, this hormonosensitivity, most of the time long, finally move on in hormonal-failure. If rare changes in the therapeutic strategy have been achieved in this setting since 2004 and the arrival of docetaxel, it is the global perception of the disease that has been modified and the definition of one specific entity: the castrate-resistant prostate cancer. This new definition and the changes of design and end-points of clinical trials testing new agents with strong recruitment during the past years have conducted to a real revolution in the management of castrate-refractory prostate cancer. The place of secondary hormonal manipulations, such as withdrawal of the anti-androgen, oestrogen or ketoconazole, still exists for a selected group of patients. In case of aggressive disease and symptoms, chemotherapy should be selected, docetaxel, in a three weeks schedule, and may be combined with Estracyt. It is time to consider the revolution of the post-chemotherapy setting with the arrival of two new drugs ; a cytotoxic one, the cabazitaxel and hormonal for the second one, the abiraterone acetate. The place of the immunotherapy with the sipuleucel-T may be more difficult to precise, especially in Europe, even if it has been finally indicated in the United States in the metastatic setting. Concerning bone metastasis, zoledronic acid was during a long time the only bone-targeted agent, effective in reducing the incidence of skeletal related events, and was recently exceeded by the denosumab, an anti-RANK ligand. Finally, let us hope that other changes will be achieved in the near future, with the cabazitaxel-docetaxel confrontation in the first-line setting, and the introduction of the abiraterone acetate before chemotherapy with docetaxel, already tested in ongoing trials.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Density Conservation Agents; Bone Neoplasms; Cancer Vaccines; Denosumab; Diphosphonates; Docetaxel; Estramustine; Humans; Imidazoles; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts; Zoledronic Acid

Prostate cancer is the most common non-cutaneous neoplasm in the male population worldwide. It is typically diagnosed in its early stages, and the disease exhibits a relatively indolent course in most patients. Despite the curability of localized disease with prostatectomy and radiation therapy, some patients develop metastatic disease and die. Although androgen deprivation is present in the majority of patients with metastatic prostate cancer, a state of androgen resistance eventually develops. Castration-resistant prostate cancer, defined when there is progression of disease despite low levels of testosterone, requires specialized care, and improved communication between medical and urologic oncologists has been identified as a key component in delivering effective therapy. Despite being considered a chemoresistant tumor in the past, the use of a prostate-specific antigen has paved the way for a new generation of trials for castration-resistant prostate cancer. Docetaxel is a life-prolonging chemotherapy that has been established as the standard first-line agent in two phase III clinical trials. Cabazitaxel, a novel taxane with activity in cancer models resistant to paclitaxel and docetaxel, is the only agent that has been compared to a chemotherapy control in a phase III clinical trial as a second-line therapy; it was found to prolong the overall survival of patients with castration-resistant prostate cancer previously treated with docetaxel when compared to mitoxantrone. Other agents used in this setting include abiraterone and sipuleucel-T, and novel therapies are continually being investigated in an attempt to improve the outcome for patients with castration-resistant prostate cancer.

Topics: Androgen Antagonists; Androstenes; Androstenols; Antineoplastic Agents; Clinical Trials as Topic; Disease Progression; Docetaxel; Evidence-Based Medicine; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts

What's known on the subject? and What does the study add? Metastatic castrate-resistant prostate cancer (mCRPC) was historically considered to be an aggressive disease resistant to conventional anticancer therapy. Within the last decade the outlook has changed beyond recognition; docetaxel chemotherapy is now firmly established as a well-tolerated treatment with significant survival benefits. Building on this, more recently there have been several landmark developments using various approaches in patients whose disease has progressed despite previous chemotherapy. Cabazitaxel chemotherapy offers survival and health-related quality of life (HRQL) improvements in this setting, as does the CYP inhibitor abiraterone acetate. Significant clinical benefits are also seen with novel radioisotope and immunotherapeutic approaches. There have been many developments in the management of this condition within the last 2 years, with several landmark studies showing new treatments that offer survival and HRQL benefits even in the setting of advanced disease, which has been heavily pretreated. This review article summarises these important developments and gives the reader an overview of current practice, recent changes and future directions. With current and forthcoming developments in the treatment of metastatic castrate-resistant prostate cancer (mCRPC) post-docetaxel, we are embarking on an age of potential 'chronic' management of this disease. It is hoped that the survival benefits associated with the various treatments, cytotoxic, hormonal and immunotherapeutic, will prove to be additive, providing a multimodal continuum of care. If so, it will be necessary to determine the optimal sequence and timing of the new treatments. One key factor in this regard is likely to be the patient's performance status and hence his eligibility for cytotoxic intervention. If chemotherapy is offered early in the post-docetaxel pathway, the patient may still be able to benefit from non-chemotherapeutic options subsequently. However, if this stage of management begins with a non-chemotherapeutic option, there is a risk that the patient's performance status will decline before he has an opportunity to benefit from chemotherapy. Further studies and ongoing clinical experience are likely to clarify this important issue, and help clinicians to maximise the survival of men with mCRPC post-docetaxel.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Taxoids

Cabazitaxel, a novel taxane, was approved in June 2010 by the U.S. Food and Drug Administration for treatment of metastatic castrate-resistant prostate cancer (mCRPC) in men previously treated with docetaxel. In TROPIC (N = 755), an open-label, randomized, phase III trial, cabazitaxel (plus prednisone) was associated with improvement in median overall survival compared with mitoxantrone plus prednisone (15.1 versus 12.7 months, p < 0.0001) in patients with mCRPC who had progressed following docetaxel-based regimens. That corresponds to a 30% relative reduction in risk of death compared with the mitoxantrone regimen. In addition, significant benefit existed in median progression-free survival with cabazitaxel versus the mitoxantrone regimen (2.8 versus 1.4 months, p < 0.0001). Most common adverse events (AEs) associated with cabazitaxel were hematologic; the rates (all grade) of neutropenia, leukopenia, and anemia were greater than 90%. Diarrhea, fatigue, asthenia, and back pain were the most common grade 3 or higher nonhematologic AEs. Because expected AEs from cabazitaxel therapy can delay or even interrupt treatment, oncology nurses need to be aware of those risks and their management. This article reviews the vital role of nurses in identifying patients at high risk for AEs associated with cabazitaxel therapy and reviews strategies for prevention and management of symptoms.

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Fatigue; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Male; Neutropenia; Nursing Assessment; Oncology Nursing; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Risk Assessment; Taxoids

The treatment landscape for men with castration-resistant prostate cancer (CRPC) is undergoing significant changes; a redefinition of the respective roles of oncologists and urologists will probably occur. In addition, the advent of the multidisciplinary team or coordinated-care approach, which has been gathering momentum over the last decade, will become not simply a preference but a clear necessity. In the present review, we explore the current wave of new treatments and describe the possibility of more complex approaches to combined therapy. New treatment options include abiraterone acetate, cabazitaxel, MDV3100 (in development), radium-223 (in development) and sipuleucel-T. We also present the traditional roles of the urologist and oncologist in caring for patients with CRPC and discuss how these may change. Compounding the new potential for treatment success, as well as the complexity of therapeutic strategies, is the emergence of novel biomarkers to evaluate treatment efficacy and to assist in patient prognosis. The prospects for successful treatment of patients with CRPC have developed considerably so that these patients may soon have a reasonable expectation of therapeutic efficacy and meaningful extension of their lives.

Topics: Abiraterone Acetate; Administration, Oral; Androgen Receptor Antagonists; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biomarkers, Tumor; Humans; Male; Medical Oncology; Nitriles; Orchiectomy; Palliative Care; Phenylthiohydantoin; Physician's Role; Professional Practice; Prostatic Neoplasms; Taxoids; Therapies, Investigational; Tissue Extracts; Urology

Current landscape of treatment of castration-resistant prostate cancer (CRPC) has recently changed. Cabazitaxel, a new taxane with potential antineoplastic activity, has been approved by Food and Drug Administration (FDA) after docetaxel failure. In a phase III trial, cabazitaxel showed increased overall survival (OS) compared with mitoxantrone (15.1 vs. 12.7 mo, HR 0.70, 95% CI 0.59-0.83, p < 0.0001). Furthermore, chemotherapy is not the only strategy available: several studies have shown as CRPC remains dependent on androgen receptor function for growth. Abiraterone acetate, an irreversible inhibitor of CYP17, has also been approved by FDA after docetaxel failure. In a phase III trial comparing abiraterone acetate to placebo, abiraterone showed improvement in OS (14.8 vs. 10.4 mo, HR 0.65, 95% CI 0.54-0.77; p < 0.0001). This review will discuss current options and the ongoing trials for second-line treatment of CRPC including chemotherapy, hormonal therapies, antiangiogenetic and immune strategies.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Immunotherapy; Male; Orchiectomy; Prostatic Neoplasms; Taxoids

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents; Cancer Vaccines; Humans; Male; Neoplasm Grading; Prostatic Neoplasms; Taxoids; Tissue Extracts

The landscape of treatment for advanced prostate cancer is continually evolving as new therapies are developed and guidelines are constantly updated. However, the management of older men with advanced disease is not optimal. Many men are denied chemotherapy based on their chronological age, not their health status. Androgen-deprivation therapy (ADT) remains the mainstay of first-line treatment of advanced disease. Once the disease becomes resistant to castration, docetaxel-based chemotherapy is the regulatory-approved standard of care, irrespective of age. The place of weekly docetaxel in patients with poor performance status and signs of frailty has to be further evaluated in clinical studies. New treatments are now available, or on the horizon, for disease that progresses during or after docetaxel therapy. Cabazitaxel and abiraterone have been shown to prolong survival, irrespective of age, and are already in clinical use having received regulatory approval. The optimal sequence for these two agents is still unknown, although there is some indication that in patients predicted to be poor responders to abiraterone (high Gleason score, progression during docetaxel therapy, rapid progression to castrate-resistant prostate cancer with ADT) cabazitaxel should be the preferred choice. Further advances are being investigated, with promising data reported from phase III trials.

Topics: Aged; Androgen Antagonists; Androstenes; Androstenols; Antineoplastic Agents; Castration; Clinical Trials as Topic; Disease Management; Docetaxel; Drug Resistance, Neoplasm; Humans; Life Expectancy; Male; Prostate; Prostatic Neoplasms; Taxoids; Treatment Outcome

Prostate Cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death in men in the Western World. Docetaxel-based chemotherapy has been the mainstay of treatment until a few years ago for metastatic castration resistant prostatic cancer (mCRPC). Recently, a broad range of therapeutic options has become available for mCRPC in a variety of settings, including chemotherapeutic agents (cabazitaxel), androgen synthesis inhibitors (abiraterone acetate), androgen receptor (AR) inhibitors (enzalutamide) and immunotherapy (sipuleucel-T). Multiple novel targeted agents are at an advanced stage of experimentation, including androgen synthesis inhibitors (TAK700), AR inhibitors (ARN509), radiopharmaceuticals (radium-223) and immunotherapeutic agents (poxvirus-based vaccine, ipilimumab). This review describes in detail the latest results obtained with a the most promising agents in prostate cancer, with a focus on CRPC biology and mechanism of resistance to anti-neoplastic treatment.

Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Cancer Vaccines; Clinical Trials as Topic; Humans; Male; Orchiectomy; Prostatic Neoplasms; Radiopharmaceuticals; Taxoids

• The treatment of metastatic and castration-resistant prostate cancer (CRPC) has advanced considerably from the era where it was considered that the disease was resistant to chemotherapy. • Cytotoxic chemotherapy involving docetaxel is now used routinely as a first-line therapy after failed first- and second-line androgen deprivation in advanced disease, improving quality of life and to a limited extent, survival in patients with advanced prostate cancer. • The cytotoxic taxane, cabazitaxel has also become a second-line treatment option for patients with CRPC failing previous docetaxel therapy. • Additionally, a broad range of agents are now available or under development including immune-based therapies (cellular therapies and vaccines), bone-targeting agents (anti-osteolytic and anti-tumour therapies) and molecular-based agents targeting cellular control mechanisms. • Most of these remain experimental but on-going pharmacological development will inevitably provide urologists and urological oncologists with a broader range of therapeutic options for better cancer management in the future.

Topics: Antineoplastic Agents; Docetaxel; Drug Design; Endothelin Receptor Antagonists; Humans; Immunotherapy; Male; Molecular Targeted Therapy; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Research; Taxoids; Treatment Outcome

The health-related quality-of-life (HRQOL) implications of advanced metastatic prostate cancer are variable. There are several different HRQOL instruments that measure domains germane to patients with advanced metastatic disease. The burden of prostate cancer is inversely related to the magnitude of HRQOL declines. Treatment with androgen deprivation therapy commonly results in HRQOL declines that have served as the impetus for intermittent therapy. Conversely, chemotherapeutic agents have been associated with improvements in functional status for men with castrate-resistant disease. Emerging therapies may result in significant HRQOL improvements in this population, and careful prospective evaluation of patient-reported outcomes will be required.

Topics: Androgen Antagonists; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone Neoplasms; Denosumab; Diphosphonates; Disease Progression; Docetaxel; Health Status Indicators; Humans; Imidazoles; Male; Mitoxantrone; Prostatic Neoplasms; Quality of Life; Taxoids; Treatment Outcome; Zoledronic Acid

Prostate cancer is the most common male cancer and one of the top causes of male cancer-related death in Western countries. Most patients with prostate cancer respond to initial androgen deprivation therapy but eventually progress to castration-resistant prostate cancer (CRPC). Although androgen receptor signaling remains the main driver in CRPC, a growing body of evidence suggests that other pathways are involved in this progression. This article reviews the preclinical data and current status of clinical trials therapeutically targeting tubulin, DNA repair, molecular chaperones such as CLU and Hsp27, tyrosine kinases, and DNA repair.

Topics: Bone Neoplasms; Cell Proliferation; Cell Survival; Dasatinib; Disease Progression; DNA Repair; Epothilones; Gene Fusion; Humans; Male; Neoplasm Invasiveness; Prostatic Neoplasms; Proto-Oncogene Proteins c-met; Pyrimidines; Receptors, Androgen; Taxoids; Thiazoles

The treatment of metastatic castration-resistant prostate cancer has evolved since the approval of docetaxel-based therapy. Since docetaxel approval, three new agents have gained approval for this indication: sipuleucel-T, cabazitaxel, and abiraterone. Recent Phase III trials have also demonstrated survival benefits for MDV-3100 and radium-223 though regulatory approval ispending. Practicing physicians face the challenge of determining the optimal sequencing of these new agents. This dilemma is particularly relevant to the post-docetaxel setting, in which the indication for several of these agents overlaps. This article details the efficacy and safety of these agents to provide a framework for their clinical use.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Benzamides; Docetaxel; Humans; Male; Neoplasms, Hormone-Dependent; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Radium; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Taxoids; Treatment Failure

Metastatic castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Prior to 2010, docetaxel chemotherapy was the only treatment shown to improve overall survival, symptom control and quality of life in patients with CRPC. Research efforts focused on overcoming chemoresistance to taxanes eventually led to the development of multiple novel anti-tumor agents, including cabazitaxel. Cabazitaxel has recently been shown to significantly improve overall survival compared with mitoxantrone in a large multicenter Phase III study. This article details the preclinical and clinical development of cabazitaxel and discusses the importance of this novel chemotherapy in CRPC. The authors also discuss the challenges now facing the future use of cabazitaxel in CRPC, including the determination of the optimal dose of cabazitaxel in patients with advanced CRPC, the ideal sequencing of cabazitaxel relative to other anti-tumor treatments, appropriate patient selection and novel strategies for the assessment of treatment response.

Topics: Antineoplastic Agents; Biological Availability; Clinical Trials as Topic; Disease Progression; Disease Resistance; Drug Evaluation, Preclinical; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Orchiectomy; Postoperative Complications; Prostatic Neoplasms; Taxoids; Treatment Outcome

To review the activity of 3 new agents approved for the management of advanced castration-resistant prostate cancer (CRPC): sipuleucel-T, cabazitaxel, and abiraterone acetate.. Literature was accessed through MEDLINE (1977-June 2012) and abstracts from the American Society of Clinical Oncology (2000-2012) using the terms castration-resistant and hormone-refractory prostate cancer, sipuleucel-T, cabazitaxel, abiraterone, Provenge, Jevtana, and Zytiga. Reference citations from publications identified were also reviewed.. Articles identified from the data sources in English on human subjects were evaluated.. Options for patients with CRPC have been limited, with little to offer those who failed or could not tolerate docetaxel-based therapy. Three new drugs, with very different mechanisms of action, have changed that and will undoubtedly change the treatment paradigm for these patients. Each agent has demonstrated an impact on patient survival. Sipuleucel-T, the first immunotherapy approved for treatment of CRPC, improved median overall survival by 4.1 months and reduced the risk of death by 22% in a placebo-controlled trial of asymptomatic patients. Sipuleucel-T can be administered prior to docetaxel-based therapy. Cabazitaxel, a taxane chemotherapy agent, improved median overall survival by 2.4 months and reduced the risk of death by 30% in a Phase 3 trial of patients whose cancer progressed during or after docetaxel-based therapy. Abiraterone acetate, a hormonal therapy, improved median overall survival by 3.9 months and reduced the risk of death by 35% in patients with relapse during or after docetaxel-based therapy.. The advent of new agents for the management of advanced CRPC has increased the choices for patients whose options were limited. Additional experience will determine the optimal sequencing of these agents, their roles in combination therapy, and their activity in patients with earlier disease.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Castration; Humans; Male; Prostatic Neoplasms; Taxoids; Tissue Extracts

Brain metastases from prostate cancer (PC) seem to be more frequent than in the past, possibly because advances in the treatment of patients with castration-resistant PC have prolonged their survival. Furthermore, docetaxel (the drug of choice for the first-line treatment of castration-resistant PC) cannot cross the blood-brain barrier and control metastatic foci. However, this problem may be overcome by new active drugs such as cabazitaxel.

Topics: Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Docetaxel; Humans; Male; Prostatic Neoplasms; Taxoids

Prostate cancer is the leading cause of cancer and second leading cause of death among men. Management of localized disease is fairly straight-forward, but treatment for locally advanced or metastatic disease is much less so. Androgen-deprivation therapy serves as the foundation of treatment for patients with locally advanced or metastatic disease. Although most patients with prostate cancer show a response to medical or surgical castration, many eventually experience a hormone-refractory, incurable state. Until recently, therapeutic options for CRPC have been limited and focused on systemic chemotherapeutic options. Unfortunately, however, this provides a minimal increase in overall survival, at the cost of significant additional toxicities. Therefore, much research has gone into developing other suitable therapies with potentially less toxicity. This article uses a case study approach to discuss new options for the treatment of castration-resistant prostate cancer.

Topics: Aged; Androgen Antagonists; Androgens; Androstenes; Androstenols; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Humans; Immunotherapy; Male; Prostatectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts; Treatment Outcome

Prostate cancer is a frequently diagnosed male cancer. In men presenting locally advanced or metastatic disease, the mainstay of treatment is hormonal suppression. Despite the castrate levels of testosterone, with time, prostate cancer gradually evolves into a castration-refractory state. Chemotherapeutic agents are able to influence the natural history of metastatic castration-resistant prostate cancer. Docetaxel is a clinically relevant, FDA-approved taxane. Today, it is the first-line chemotherapeutic agent in castration-refractory prostate cancer (CRPC). There is no standard second-line chemotherapeutic regimen.. This review provides information on the efficacy of cabazitaxel as a second-line treatment for CRPC. The medline database was searched for clinical trials on chemotherapeutical treatment options of castration-resistant prostate cancer. All available data on the efficacy of cabazitaxel are summarized.. New treatment strategies for castration-resistant prostate cancer should primarily focus on quality of life. In this view, vaccination therapy seems promising because of the acceptable level of toxicity. However, more research is needed to prove their efficacy in the treatment of castration-resistant prostate cancer. Cabazitaxel seems to be a promising second-line therapy in CRPC.

Topics: Antineoplastic Agents; Cancer Vaccines; Clinical Trials as Topic; Combined Modality Therapy; Humans; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Quality of Life; Taxoids

Treatment of metastatic castrate resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy is a challenging clinical scenario with limited availability of treatment options. Re-treatment with docetaxel, either as monotherapy or in combination with other cytotoxics or targeted agents has shown durable responses. However, most docetaxel re-treatment studies have been either retrospective or early phase non-randomised studies which have not formally assessed Quality of life or survival gain with re-treatment. Despite limited evidence for efficacy of mitoxantrone in the second-line, it continues to remain widely used, largely due to lack of available suitable alternatives. Cabazitaxel in combination with prednisolone is the only chemotherapy to have shown a significant survival benefit and receive approval by the U.S. Food and Drug Administration for patients with mCRPC previously treated with a docetaxel-based regimen. Abiraterone acetate has recently demonstrated a significant improvement in survival when compared to placebo in patients with docetaxel-treated mCRPC. This review aims to summarize the current evidence and discuss future strategies for treatment of mCRPC patients following failure of docetaxel chemotherapy.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease Progression; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Forecasting; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Prednisolone; Prostatic Neoplasms; Quality of Life; Taxoids; Treatment Failure

Our understanding of - as well as our approach to - castration resistant prostate cancer is currently undergoing major changes. New drugs like the CYP-17 inhibitor abiraterone have shown that even in the "hormone refractory" stage the progression of prostate cancer is still driven by signaling of the androgen receptor. Changing the term to castration resistant prostate cancer is one consequence of these new insights. Here we give an overview on the current situation of drug development, therapeutic consequences and future trends.

Topics: Androgen Antagonists; Androstenes; Androstenols; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Bone Neoplasms; Cancer Vaccines; Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Ketoconazole; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Taxoids; Tissue Extracts

Until recently, patients with castration-resistant prostate cancer (CRPC) had limited therapeutic options once they became refractory to docetaxel chemotherapy, and no treatments improved survival. This changed in June 2010 when the Food and Drug Administration (FDA) approved cabazitaxel as a new option for patients with CRPC whose disease progresses during or after docetaxel treatment. For most of these patients, cabazitaxel will now replace mitoxantrone (a drug that was FDA-approved because of its palliative effects) as the treatment of choice for docetaxel-refractory disease. The approval of cabazitaxel was based primarily on the TROPIC trial, a large (n = 755) randomized Phase III study showing an overall median survival benefit of 2.4 months for men with docetaxel-pretreated metastatic CRPC receiving cabazitaxel (with prednisone) compared to mitoxantrone (with prednisone). Cabazitaxel is a novel tubulin-binding taxane that differs from docetaxel because of its poor affinity for P-glycoprotein (P-gp), an ATP-dependent drug efflux pump. Cancer cells that express P-gp become resistant to taxanes, and the effectiveness of docetaxel can be limited by its high substrate affinity for P-gp. Preclinical and early clinical studies show that cabazitaxel retains activity in docetaxel-resistant tumors, and this was confirmed by the TROPIC study. Common adverse events with cabazitaxel include neutropenia (including febrile neutropenia) and diarrhea, while neuropathy was rarely observed. Thus, the combination of cabazitaxel and prednisone is an important new treatment option for men with docetaxel-refractory metastatic CRPC, but this agent should be administered cautiously and with appropriate monitoring (especially in men at high risk of neutropenic complications).

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prostatic Neoplasms; Taxoids

This review will describe the contemporary management of castration-resistant prostate cancer in the context of multiple recent advances.. Two novel agents have been added to the therapeutic armamentarium including cabazitaxel and sipuleucel-T. Cabazitaxel, a novel taxane extended survival in men with progressive metastatic CRPC following conventional docetaxel-based chemotherapy. Sipuleucel-T, an autologous dendritic cell based vaccine extended survival in men with relatively asymptomatic metastatic CRPC without visceral metastasis. A third agent, abiraterone acetate, an orally administered CYP17 inhibitor, which suppresses androgen synthesis has been preliminarily reported to significantly prolong survival following prior docetaxel and approval by regulatory agencies is anticipated. Baseline and early changes in circulating tumor cells appear useful as a prognostic factor. Additionally, data demonstrated the superiority of denosumab, a RANK-ligand antagonist, compared to zoledronic acid in the prevention of skeletal related events in men with bone metastases.. Cabazitaxel, sipuleucel-T and denosumab were approved in 2010 by regulatory agencies in the USA for men with metastatic CRPC, and approval of abiraterone acetate is anticipated based on the results of a phase III trial. The evaluation of circulating tumor cells assists in determining prognosis, although its utility for clinical decision-making entails validation.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Castration; Denosumab; Drug Therapy; Humans; Male; Prostatic Neoplasms; RANK Ligand; Taxoids; Testicular Neoplasms; Tissue Extracts

Seven years passed since docetaxel/prednisone demonstrated and overall survival benefit, leading to its approval by the FDA for metastatic castration resistant prostate cancer. In 2010, two new treatments, sipuleucel-T and cabazitaxel, were approved by the United States Food and Drug Administration for men with castration-resistant prostate cancer, based upon improvement in overall survival. The progress that has been made in understanding the biological basis of disease progression, particularly the role of the continued activation of the androgen receptor, have led to new treatments that will further improve survival in these patients. Abiraterone, a drug that depletes both intracellular and extracellular sources of testosterone, demonstrated a 3.9-month improvement in survival in patients who failed docetaxel-based chemotherapy. Other drugs targeting the androgen-receptor axis, such as TAK-700 and MDV3100, have demonstrated significant activity in phase 1 and 2 studies, and are currently in phase 3. Agents that target angiogenesis, bone, and novel apoptotic proteins currently are under investigation, either as single agents or in combination with chemotherapy. The challenge for the development of clinical trials will be how these compounds will be sequenced in the future.

Topics: Androstenes; Androstenols; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Docetaxel; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Staging; Neovascularization, Pathologic; Nitriles; Phenylthiohydantoin; Prednisone; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Tissue Extracts; Treatment Outcome

The development of drug resistance is a major obstacle to effective cancer therapy. Several agents are in clinical development with the goal of overcoming resistance. Among them is cabazitaxel, a semisynthetic taxoid that is able to overcome a common mechanism of resistance that limits the efficacy of other chemotherapeutic agents, including the older taxanes. The promise of cabazitaxel as a second-line chemotherapy option for advanced prostate cancer has been confirmed clinically in the phase III TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-Containing Regimen) trial. This trial showed that cabazitaxel is the first chemotherapeutic agent to demonstrate a survival benefit in metastatic castration-resistant prostate cancer (mCRPC) since the approval of docetaxel. On this basis, the US FDA and the European Medicines Agency approved cabazitaxel in June 2010 and January 2011, respectively, for the treatment of patients with mCRPC who have previously been treated with docetaxel. The most prevalent toxicity was neutropenia and the use of primary prophylaxis with granulocyte-colony stimulating factor is recommended in high risk patients. This article presents the preliminary antitumour activity, safety, tolerability and pharmacokinetic data of cabazitaxel, and an overview of the current status of clinical development.

Topics: Animals; Antineoplastic Agents; Drug Approval; Drug Resistance, Neoplasm; Granulocyte Colony-Stimulating Factor; Humans; Male; Neoplasm Metastasis; Neutropenia; Prostatic Neoplasms; Survival; Taxoids

Castrate-resistant prostate cancer (CRPC) is the most clinically advanced form of prostate cancer. Prior to 2004, treatment options for patients with CRPC were limited to palliative care with mitoxantrone. However, two phase III trials in 2004 showed improved survival with docetaxel compared with mitoxantrone in patients with metastatic CRPC. Docetaxel remains the current standard chemotherapy for CRPC.. A literature review was conducted to ascertain agents recently approved or in development for CRPC as well as several treatment algorithms being developed in this patient population.. Recently, the US Food and Drug Administration (FDA) approved chemotherapy agents including cabazitaxel, a novel taxane, for the treatment of patients with metastatic CRPC who were previously treated with docetaxel-based chemotherapy. The immunotherapy sipuleucel-T and the androgen biosynthesis inhibitor, abiraterone, have also just been approved. A number of other novel agents are in clinical development for the management of CRPC.. Options for the management of CRPC are rapidly expanding. Based on improved survival with docetaxel in patients with CRPC, chemotherapy is being investigated for use earlier in the prostate cancer disease spectrum. Studies are actively evaluating chemotherapy in the neoadjuvant and adjuvant settings for patients with high risk, localized prostate cancer. A multidisciplinary approach towards patients with difficult-to-manage prostate cancer in which urologists familiarize themselves with these newer systemic agents and refer appropriate patients to oncologists may be beneficial.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Chemotherapy, Adjuvant; Docetaxel; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts

Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.

Topics: Androstenes; Androstenols; Angiogenesis Inhibitors; Anilides; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Atrasentan; Benzamides; Bevacizumab; Biomarkers, Tumor; Bone Remodeling; Cancer Vaccines; Clinical Trials as Topic; Clusterin; Dasatinib; Denosumab; Endothelin-1; Humans; Immunotherapy; Indoles; Ipilimumab; Male; Mice; Mice, SCID; Molecular Targeted Therapy; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms; Pyridines; Pyrimidines; Pyrroles; Pyrrolidines; RANK Ligand; Receptor Cross-Talk; Receptors, Androgen; Signal Transduction; Sunitinib; Taxoids; Thiazoles; Tissue Extracts; Treatment Failure; Tumor Microenvironment; Xenograft Model Antitumor Assays

Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen-deprivation therapy, but invariably progresses to the castration-resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen-deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first-line treatment in patients with castration-resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)-prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone-prednisone. Several other novel agents are currently being evaluated, including sipuleucel-T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell-based immunotherapy sipuleucel-T produces longer OS times in chemotherapy-naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Docetaxel; Humans; Male; Neoplasm Metastasis; Prednisolone; Prostatic Neoplasms; Radioisotopes; Taxoids; Tissue Extracts

Topics: Abiraterone Acetate; Androstadienes; Antineoplastic Agents; Benzamides; Cancer Vaccines; Disease Progression; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Tissue Extracts

Treatment options for patients with advanced prostate cancer (PCa) remain limited. Improved understanding of the underlying molecular drivers of prostate cancer pathogenesis, progression and resistance development has provided the fundamental basis for rational targeted drug design.. This review will discuss the most recent developments in the field of prostate cancer therapies including key findings such as the identification of ETS gene rearrangements, the dissection of prostate cancer molecular heterogeneity and the discovery that castration-resistant prostate cancer (CRPC) remains androgen-driven despite the androgen-depleted milieu, thus making androgen receptor signaling a continued focus of molecularly targeted treatments. A multitude of new molecularly targeted agents are in clinical development and are highly likely to change the current treatment paradigm.. This review will outline the current clinical development of molecular targeted treatments in CRPC.. Unraveling the complex molecular biology that underpins this heterogeneous disease may pave the way to personalized therapy with a wide range of rationally targeted agents and combination treatments. In conclusion, we can predict that the rational clinical development of new targeted drugs will improve the outcome of men with prostate cancer in the years ahead.

Topics: Androgen Antagonists; Animals; Antineoplastic Agents; Drug Delivery Systems; Drug Discovery; Humans; Male; Prostatic Neoplasms; Taxoids; Treatment Outcome

Docetaxel remains a cornerstone of therapy for the patient with metastatic castration-resistant prostate cancer (CRPC). However, the landscape of CRPC therapy is changing rapidly - recently, data from the phase III TROPIC study revealed a survival advantage with the novel taxane cabazitaxel/prednisone (compared with mitoxantrone/prednisone) in a cohort of 755 men with docetaxel-refractory metastatic CRPC. Interestingly, cabazitaxel bears substantial structural similiarity to docetaxel but appears to be mechanistically distinct. In preclinical studies, the agent has antitumor activity in a variety of docetaxel-refractory in vitro and in vivo models. Subsequent to phase I testing in advanced solid tumors (where neutropenia was identified as a dose-limiting toxicity), the agent was assessed in a phase II trial in advanced, taxane-refractory breast cancer and in the aforementioned phase III TROPIC study. This review describes in detail the preclinical and clinical development of cabazitaxel.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Docetaxel; Drug Resistance, Neoplasm; Female; Humans; Male; Mice; Neutropenia; Prednisone; Prostatic Neoplasms; Rats; Taxoids

The FDA's approval of docetaxel in 2004 created a clear mandate for clinical researchers to create new therapies effective for metastatic castrate-resistant prostate cancer (mCRPC) patients with progression post-docetaxel. In 2010, the first trial to prolong survival in this setting was announced using a cabazitaxel, a novel taxane. This therapeutic agent was specifically designed to have activity in model systems resistant to conventional taxanes. After phase I testing, with observation of clinically significant activity in patients with advanced cancers, cabazitaxel/prednisone was tested in a large phase III trial enrolling patients with mCRPC who had disease progression despite prior docetaxel therapy. This phase III trial TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a Taxotere-Containing Regimen), using mitoxantrone/prednisone as a control arm, demonstrated a significant improvement in survival (the primary endpoint). Both subset analyses and secondary endpoints (response rates and time to progression) were supportive of the survival findings. This trial was pivotal for the FDA's approval of the new drug application for cabazitaxel. This review focuses on both the pre-clinical and clinical development of cabazitaxel.

Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Docetaxel; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Treatment Outcome

Prostate cancer will be diagnosed in one of six men during their lifetimes, and a small portion of these will progress after primary and salvage therapies. For many years, there were few treatment options for these patients after routine hormonal maneuvers, and standard of care since the early 2000s has consisted primarily of docetaxel, which improved survival over the previous first-line therapy mitoxantrone. In recent years, however, new therapies have begun to emerge to treat this devastating form of prostate cancer. This review examines the mechanisms behind these therapeutics and the key trials seeking to validate their clinical use.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Denosumab; Humans; Immunotherapy; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; RANK Ligand; Taxoids; Tissue Extracts

Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer.. This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile.. The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078).. Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Topics: Abiraterone Acetate; Humans; Leuprolide; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms

Aggressive variant prostate cancer (AVPC) represents a clinical subset distinguished by therapy resistance and poor prognosis, linked to combined losses of the tumor suppressor genes (TSG). Genomic analysis of chromosomal copy-number alterations (CNA) at single-cell resolution was performed in CTC from patients with and without AVPC before initiating chemotherapy with cabazitaxel or cabazitaxel and carboplatin. We evaluated associations between single-CTC genomics and clinical features, progression-free survival, and overall survival.. A total of 257 individual CTC were sequenced from 47 patients (1-22 CTC/patient). Twenty patients (42.6%) had concurrent 2+TSG losses in at least one CTC in association with poor survival and increased genomic instability, inferred by high large-scale transitions scores. Higher LST in CTC were independent of CTC enumerated, clinically more indicative of aggressive behavior than co-occurring TSG losses, and molecularly associated with gains in chromosomal regions including. Our findings suggest that genomic instability in CTC is a hallmark of advanced prostate cancer aggressiveness, and support single-CTC sequencing as a compelling tool to noninvasively characterize cancer heterogeneity.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carboplatin; DNA Copy Number Variations; Genes, Tumor Suppressor; Genomic Instability; Humans; Male; Middle Aged; Neoplastic Cells, Circulating; Progression-Free Survival; Prostate; Prostatic Neoplasms; Single-Cell Analysis; Taxoids

One of the standard management options for high-risk localized prostate cancer is radiotherapy combined with long-term androgen deprivation therapy. Trials involving chemotherapy or next-generation hormone therapies in combination with a local treatment are ongoing for this specific subgroup.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Disease-Free Survival; Docetaxel; Humans; Male; Prostatic Neoplasms; Radiotherapy; Taxoids; Treatment Outcome; Tubulin Modulators

Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3-4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed "per cycle" incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis."Per cycle" incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86-0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34-0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86-1; P = 0.07). Patients with a body surface area >2 m2 presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86-1; P = 0.07), but decreased odds of having G3 to 4 anemia.Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.

Topics: Antineoplastic Agents; Humans; Male; Prostatic Neoplasms; Retrospective Studies; 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

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Castration; Cell Line, Tumor; Disease-Free Survival; Humans; Male; Mitoxantrone; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms; Taxoids; Tubulin

Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment.. We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079.. 755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia.. Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy.. Sanofi-Aventis.

Topics: Administration, Oral; Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Docetaxel; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Mitoxantrone; Neutropenia; Pain Measurement; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Failure; Treatment Outcome

The Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) protein has been indicated as an overexpressed oncoprotein in prostate cancer (PCa), associated with tumor progression and aggressiveness. Taxane-based antineoplastic drugs such as paclitaxel, docetaxel, or cabazitaxel, have been investigated in PCa treatment, namely for the development of combined therapies with the improvement of therapeutic effectiveness. This study aimed to evaluate the expression of STEAP1 in response to taxane-based drugs and assess whether the sensitivity of PCa cells to treatment with paclitaxel, docetaxel, or cabazitaxel may change when the

Topics: Antigens, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Humans; Male; Oxidoreductases; Paclitaxel; Prostate; Prostatic Neoplasms; Taxoids

: Epithelial-mesenchymal transition (EMT) is a critical mechanism that promotes cancer cells to metastasis. Therefore, EMT regulation has become an important target in anticancer therapy approaches in recent years. However, in metastatic prostate cancer (PC), the EMT regulatory effect has not fully understood for cabazitaxel (Cbx), a third line taxane-based chemotherapeutic for metastatic castration-resistant PC.. In this study, we investigated the antimetastatic and EMT-regulatory effects of Cbx on hormone-sensitive metastatic PC cells.. The anticancer effects of Cbx were assessed by WST-1 and Annexin V analysis. The antimetastatic effect of Cbx was evaluated by wound healing and quantitative reverse transcription polymerase chain reaction through EMT-mesenchymal-to-epithelial transition (MET) markers as well as EMT-repressor microRNAs (miRNAs) in Cbx-treated LNCaP cells.. Our results showed that, in addition to its apoptotic and anti-migratory activities, Cbx exhibited the EMT-repressor effects through the prominent downregulation of matrix metalloproteinase-9 and Snail levels as EMT-promoting factors, and the significant upregulation of the certain miRNAs, including miR-205, miR-524, and miR-124, which play a role in EMT-repressing by targeting regulators of the EMT-associated genes.. Although further evaluations are needed to improve the findings, we showed that, in addition to its classical taxane function, Cbx has a regulatory effect on EMT-MET cycling in hormone-sensitive metastatic PC.

Topics: Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Hormones; Humans; Male; MicroRNAs; Prostatic Neoplasms; Taxoids

Chemotherapeutic agents can have both serious side effects and ototoxicity, which can be caused by direct toxic effects or by metabolic derangement by the agents. Cabazitaxel (CBZ) is a next-generation semi-synthetic taxane derivative that is effective in both preclinical models of human tumors that are sensitive or resistant to chemotherapy and in patients suffering from progressive prostate cancer despite docetaxel treatment. The primary aim of this study is to investigate the ototoxicity of CBZ in a rat model.. : A total of 24 adult male Wistar-Albino rats were equally and randomly divided into four groups. CBZ (Jevtana, Sanofi-Aventis USA) was intraperitoneally administered to Groups 2, 3, and 4 at doses of 0.5, 1.0, and 1.5 mg/kg/week, respectively, for 4 consecutive weeks; Group 1 received only i.p. saline at the same time. At the end of the study, the animals were sacrificed and their cochlea removed for histopathological examination.. : Intraperitoneal administration of CBZ exerted an ototoxic effect on rats, and the histopathological results became worse in a dose-dependent manner (P < 0.05).. : Our findings suggest that CBZ may be an ototoxic agent and can damage the cochlea. More clinical studies should be conducted to understand its ototoxicity.

Topics: Animals; Antineoplastic Agents; Cochlea; Humans; Male; Ototoxicity; Prostatic Neoplasms; Rats; Rats, Wistar

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

Cancer stem cells (CSCs) are associated with metastasis and recurrence in prostate cancer as well as other cancers. We aimed to enhance the sensitivity of cabazitaxel in prostate cancer cell therapy by targeting CSCs with a Wnt inhibitor and salinomycin pretreatment. PC3, DU-145, and LNCaP human prostate cancer cells were exposed to Wnt/β-catenin pathway inhibitor CCT036477 (iWnt) with salinomycin for 48 h, followed by cabazitaxel treatment for 48 h. Cell viability, mRNA, and protein expression changes were evaluated by MTT, RT-qPCR, and Western blot assays, respectively. Apoptosis was determined by image-based cytometry, and cell migration was assessed by wound healing assay. Three-dimensional culture was established to assess the malignant phenotype and stemness potential of transformed or cancer cells. CD44 + CSCs were isolated using magnetic-activated cell sorting system. Pretreatment of PC3, DU-145, and LNCaP cells with salinomycin iWnt significantly sensitized the cells to cabazitaxel therapy. Spheroid culture confirmed that the treatment modality was more effective than a single administration of chemotherapy. The pretreatment of PC3 cells increased the rate of apoptosis compared to single administration of cabazitaxel, which downregulated Bcl-2 and upregulated caspase 3, caspase 8 expressions. The pretreatment suppressed cell migration, downregulated the expression of Sox2 and Nanog, and significantly reduced CD44 + CSC numbers. Notably, the treatment modality reduced pAKT, p-P38 MAPK, and pERK1/2. The data suggest that pretreatment of prostate cancer cells with salinomycin and Wnt inhibitor may increase the efficacy of cabazitaxel therapy by inhibiting cell proliferation and migration, and eliminating cancer stem cells.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Male; Neoplastic Stem Cells; Prostatic Neoplasms; Wnt Signaling Pathway

Topics: Carcinoma; Castration; Humans; Male; Prostate; Prostatic Neoplasms

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

Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.

Topics: Animals; Dextrans; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Unsaturated; Humans; Male; Mice; Mice, Nude; Prostatic Neoplasms; Water

Tumor-initiating or cancer stem cells (CSCs) reduce the effectiveness of conventional therapy. Thus, it is crucial to eliminate CSCs while killing bulky cancer cells using a combination of conventional chemotherapy and anti-CSC drugs. Salinomycin is a selective inhibitor against CSCs and shows promise in combination applications. The aim of the study was to examine the efficacy of co-administered cabazitaxel and salinomycin on the survival of prostate cancer cells and CSCs.. CD44 + stem cells were isolated from human PC3 prostate cancer cells by using magnetic activated cell sorting. The cells were concomitantly exposed to salinomycin and cabazitaxel, and the cell survival was determined by MTT test. Apoptosis was assessed by image-based cytometer, and cell migration was evaluated by wound healing assay. The expression of target mRNA and protein were assessed by RT-qPCR and Western blot, respectively. Combination index (CI) analysis showed that simultaneous administration of salinomycin and cabazitaxel was able to exert strong synergistic effect on CD44 + subpopulation (CI = 0.33), but no synergism was observed in PC3 cells. The combination of the two agents significantly increased Bax, cytochrome c, caspase-3 and - 8 mRNA expression in CD44 + CSCs, causing apoptosis. The applied therapy strategy strongly inhibited the phosphorylation of Akt, protein expression of Akt1, NF-κB and Wnt.. In conclusion, our data suggest that combining salinomycin with cabazitaxel shows promise as a prostate cancer treatment approach that can target CSCs.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Humans; Hyaluronan Receptors; Male; Neoplastic Stem Cells; NF-kappa B; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrans; RNA, Messenger; Taxoids

The androgen receptor (AR) pathway is a key driver of neoplastic behaviour in the different stages of metastatic prostate cancer (mPCa). Targeting the AR therefore remains the cornerstone for mPCa treatment. We have previously reported that activation of AR signalling affects taxane chemo-sensitivity in preclinical models of castration resistant PCa (CRPC). Here, we explored the anti-tumour efficacy of the AR targeted inhibitor enzalutamide combined with cabazitaxel.. We used the AR positive CRPC model PC346C-DCC-K to assess the in vitro and in vivo activity of combining enzalutamide with cabazitaxel. Subsequent validation studies were performed using an enzalutamide resistant VCaP model. To investigate the impact of AR signalling on cabazitaxel activity we used quantitative live-cell imaging of tubulin stabilization and apoptosis related nuclear fragmentation.. Enzalutamide strongly amplified cabazitaxel anti-tumour activity in the patient-derived xenograft models PC346C-DCC-K (median time to humane endpoint 77 versus 48 days, P<0.0001) and VCaP-Enza-B (median time to humane endpoint 80 versus 53 days, P<0.001). Although enzalutamide treatment by itself was ineffective in reducing tumour growth, it significantly suppressed AR signalling in PC346C-DCC-K tumours as shown by AR target gene expression. The addition of enzalutamide enhanced cabazitaxel induced apoptosis as shown by live-cell imaging (P<0.001).. Our study demonstrates that cabazitaxel efficacy can be improved by simultaneous blocking of AR signalling by enzalutamide, even if AR targeted treatment no longer affects tumour growth. These findings support clinical studies that combine AR targeted inhibitors with cabazitaxel in CRPC.

Topics: Androgen Receptor Antagonists; Androgens; Animals; Apoptosis; Benzamides; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Fluorescent Antibody Technique; Humans; Male; Mice; Microtubules; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Taxoids; Xenograft Model Antitumor Assays

Our previous report has shown that the flavonoid 2'-hydroxyflavanone (2'-HF) showed inhibition of androgen receptor (AR) activity against androgen-sensitive prostate cancer (PCa) cells, LNCaP, and exhibited antitumor effects against androgen-insensitive PCa cells, PC-3, and DU145. In the present study, we prepared a derivative of 2'-HF, 16MS7F1924, and confirmed the effects of this derivative on PCa cells.. The antiproliferation effects of 16MS7F1924 were investigated in PCa cells using LNCaP, PC-3, DU145 and docetaxel-resistant and cabazitaxel-resistant cell lines of PC-3-TxR/CxR and DU145-TxR/CxR. Prostate-specific antigen (PSA) and AR expression level in whole cells and the nucleus were confirmed in LNCaP by reverse transcriptase polymerase chain reaction and Western blot analysis. AR activity in LNCaP cells was confirmed by luciferase assay using PSA promoter-driven reporter. To analyze the antiproliferative effects, cell-based assays using flow cytometry, immunocytochemistry, and TUNEL assay as well as Western blot analysis were employed. Furthermore, PC-3, DU145 and each chemoresistant strain of human PCa cells were subcutaneously xenografted. The antitumor effects of 16MS7F1924 were evaluated in vivo.. 16MS7F1924 showed antitumor effect on all PCa cells in a dose-dependent manner. 16MS7F1924 reduced the expression of PSA messenger RNA (mRNA) and protein and inhibited AR activity in a dose-dependent manner, while expression of AR protein and mRNA was reduced by 16MS7F1924. 16MS7F1924 induced mitotic catastrophe and apoptosis. Apoptotic cells were increased in a dose-dependent manner, and the apoptosis was mediated through the Akt pathway. Tumor growth was safely and significantly inhibited by both intraperitoneal and oral administration of 16MS7F1924 in vivo.. 16MS7F1924 had sufficient antitumor activity against androgen-sensitive and cabazitaxel-resistant PCa cells and may be useful as a novel therapeutic agent overcoming hormone- and chemoresistant PCas.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Flavanones; Humans; Male; Mice; Mice, SCID; Molecular Structure; PC-3 Cells; Prostatic Neoplasms; Taxoids; Xenograft Model Antitumor Assays

Delivery of drugs and nanomedicines to tumors is often heterogeneous and insufficient and, thus, of limited efficacy. Microbubbles in combination with ultrasound have been found to improve delivery to tumors, enhancing accumulation and penetration. We used a subcutaneous prostate cancer xenograft model in mice to investigate the effect of free and nanoparticle-encapsulated cabazitaxel in combination with ultrasound and microbubbles with a lipid shell or a shell of nanoparticles. Sonopermeation reduced tumor growth and prolonged survival (26%-100%), whether the free drug was co-injected with lipid-shelled microbubbles or the nanoformulation was co-injected with lipid-shelled or nanoparticle-shelled microbubbles. Coherently with the improved therapeutic response, we found enhanced uptake of nanoparticles directly after ultrasound treatment that lasted several weeks (2.3 × -15.8 × increase). Neither cavitation dose nor total accumulation of nanoparticles could explain the variation within treatment groups, emphasizing the need for a better understanding of the tumor biology and mechanisms involved in ultrasound-mediated treatment.

Topics: Animals; Combined Modality Therapy; Drug Delivery Systems; Heterografts; Male; Mice; Mice, Inbred BALB C; Microbubbles; Nanoparticles; Prostatic Neoplasms; Taxoids; Treatment Outcome; Ultrasonic Therapy

Cabazitaxel (CBZ) is now widely used for prostate cancer (PC) patients resistant to docetaxel (DOC), however, most patients eventually acquire resistance. It will, therefore, be of great benefit to discover novel therapeutic target for the resistance. We aimed to identify candidate therapeutic targets for CBZ-resistance by proteomic analysis of extracellular vesicles (EVs) isolated from serum of DOC-resistant PC patients who later developed CBZ-resistance as well as those harvested from culture medium of DOC- and CBZ-resistant PC cell lines.. Using T-cell immunoglobulin domain and mucin domain-containing protein 4 (Tim4) conjugated to magnetic beads, EVs were purified from serum of PC patients with DOC-resistance that was collected before and after acquiring CBZ-resistance and conditioned medium of DOC-resistant (22Rv1DR) and CBZ-resistant (22Rv1CR) PC cell lines. Protein analysis of EVs was performed by nanoLC-MS/MS, followed by a comparative analysis of protein expression and network analysis. The cytotoxic effect of a phosphatidylinositol-3-kinase (PI3K) inhibitor, ZSTK474, was evaluated by WST-1 assay. The expression and phosphorylation of PI3K and PTEN were examined by western blot analysis.. Among differentially regulated proteins, 77 and 61 proteins were significantly increased in EVs from CBZ-resistant PC cell line and patients, respectively. A comparison between the two datasets revealed that six proteins, fructose-bisphosphate aldolase, cytosolic nonspecific dipeptidase, CD63, CD151, myosin light chain 9, and peroxiredoxin-6 were elevated in EVs from both cell line and patients. Network analysis of the increased EV proteins identified pathways associated with CBZ-resistance including PI3K signaling pathway. ZSTK474 significantly inhibited growth of 22Rv1CR cells and improved their sensitivity to CBZ. In 22Rv1CR cells, PI3K was activated and PTEN that inhibits PI3K was deactivated.. Proteomic analysis of serum EVs was successfully accomplished by using Tim-4 as a tool to isolate highly purified EVs. Our results suggest that the combination use of CBZ and PI3K inhibitor could be a promising treatment option for CBZ-resistant PC patients.

Topics: Antineoplastic Agents; Cell Line, Tumor; Docetaxel; Drug Discovery; Drug Resistance, Neoplasm; Extracellular Vesicles; Humans; Male; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms; Proteomics; Signal Transduction; Taxoids

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

Nanoparticles composed of poly(alkyl cyanoacrylate) (PACA) have shown great promise due to their biodegradability and high drug loading capacity. Development of optimal PACA nanocarriers requires detailed analysis of the overall cellular impact exerted by PACA variants. We here perform a comprehensive comparison of cabazitaxel (CBZ)-loaded nanocarriers composed of three different PACA monomers, i.e. poly(n-butyl cyanoacrylate) (PBCA), poly(2-ethylbutyl cyanoacrylate) (PEBCA) and poly(octyl cyanoacrylate) (POCA). The cytotoxicity of drug-loaded and empty PACA nanoparticles were compared to that of free CBZ across a panel of nine cancer cell lines by assessing cellular metabolism, proliferation and protein synthesis. The analyses revealed that the cytotoxicity of all CBZ-loaded PACAs was similar to that of free CBZ for all cell lines tested, whereas the empty PACAs exerted much lower toxicity. To increase our understanding of the toxic effects of these treatments comprehensive MS-based proteomics were performed with HCT116, MDA-MB-231 and PC3 cells incubated with PACA-CBZ variants or free CBZ. Interestingly, PACA-CBZ specifically led to decreased levels of proteins involved in focal adhesion and stress fibers in all cell lines. Since we recently demonstrated that encapsulation of CBZ within PEBCA nanoparticles significantly improved the therapeutic effect of CBZ on a patient derived xenograft model in mice, we investigated the effects of this PACA variant more closely by immunoblotting. Interestingly, we detected several changes in the protein expression and degree of phosphorylation of SRC-pathway proteins that can be relevant for the therapeutic effects of these substances.

Topics: Animals; Colon; Cyanoacrylates; Drug Carriers; Humans; Male; Mice; Nanoparticles; Prostatic Neoplasms; Proteome; Taxoids

Cabazitaxel is known to be effective in patients with castration-resistant prostate cancer (CRPC) showing resistance to docetaxel. The objective of this study was to investigate the molecular mechanism mediating cytotoxic activity of cabazitaxel in docetaxel-resistant human CRPC cells.. Parental human CRPC cell line PC3 (PC3/P) was continuously exposed to increasing doses of docetaxel, and a cell line resistant to docetaxel, PC3/R, was developed. Phenotypic differences between these cell lines were investigated.. There were no significant differences in sensitivity to cabazitaxel between PC3/P and PC3/R. In PC3/P, both docetaxel and cabazitaxel markedly inhibited the phosphorylation of AKT serine/threonine kinase 1 (AKT) and p44/42 mitogen-activated protein kinase (MAPK). In PC3/R, however, phosphorylation of AKT and p44/42 MAPK were maintained following treatment with docetaxel, whereas treatment with cabazitaxel resulted in the marked down-regulation of phosphorylation of AKT but not that of p44/42 MAPK. Furthermore, additional treatment of PC3/R with a specific inhibitor of AKT significantly enhanced the cytotoxic activity of docetaxel but not that of cabazitaxel. Growth of PC3/R in nude mice after treatment with cabazitaxel was significantly inhibited compared with that after treatment with docetaxel.. Antitumor activity of cabazitaxel in docetaxel-resistant CRPC cells was explained, at least in part, by the inactivation of persistently phosphorylated AKT even after treatment with docetaxel.

Topics: Animals; Antineoplastic Agents; Chromones; Docetaxel; Drug Resistance, Neoplasm; Humans; Ki-67 Antigen; Male; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1; Morpholines; PC-3 Cells; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Taxoids; Xenograft Model Antitumor Assays

Overcoming taxane resistance remains a major clinical challenge in metastatic castrate-resistant prostate cancer (mCRPC). Loss of DNA repair proteins is associated with resistance to anti-microtubule agents. We propose that alterations in DNA damage response (DDR) pathway contribute to taxane resistance, and identification of these alterations may provide a potential therapeutic target to resensitize docetaxel-refractory mCRPC to taxane-based therapy.. Alterations in DDR gene expression in our prostate cancer cell line model of docetaxel-resistance (DU145-DxR) derived from DU-145 cells were determined by DDR pathway-specific polymerase chain reaction array and immunoblotting. The PRKDC gene encoding DNA-PKc (DNA-dependent protein kinase catalytic unit), was noted to be overexpressed and evaluated for its role in docetaxel resistance. Cell viability and clonogenic survival of docetaxel-treated DU145-DxR cells were assessed after pharmacologic inhibition of DNA-PKc with three different inhibitors-NU7441, LTURM34, and M3814. Response to second-line cytotoxic agents, cabazitaxel and etoposide upon DNA-PKc inhibition was also tested. The impact of DNA-PKc upregulation on DNA damage repair was evaluated by comet assay and analysis of double-strand breaks marker, γH2AX and Rad51. Lastly, DNA-PKc inhibitor's effect on MDR1 activity was assessed by rhodamine 123 efflux assay.. DDR pathway-specific gene profiling revealed significant upregulation of PRKDC and CDK7, and downregulation of MSH3 in DU145-DxR cells. Compared to parental DU145, DU145-DxR cells sustained significantly less DNA damage when exposed to etoposide and docetaxel. Pharmacologic inhibition of DNA-PKc, a component of NHEJ repair machinery, with all three inhibitors, significantly resensitized DU145-DxR cells to docetaxel. Furthermore, DNA-PKc inhibition also resensitized DU145-DxR to cabazitaxel and etoposide, which demonstrated cross-resistance. Inhibition of DNA-PKc led to increased DNA damage in etoposide- and docetaxel-treated DU145-DxR cells. Finally, DNA-PKc inhibition did not affect MDR1 activity, indicating that DNA-PKc inhibitors resensitized taxane-resistant cells via an MDR1-independent mechanism.. This study supports a role of DDR genes, particularly, DNA-PKc in promoting resistance to taxanes in mCRPC. Targeting prostatic DNA-PKc may provide a novel strategy to restore taxane sensitivity in taxane-refractory mCRPC.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chromones; DNA Damage; DNA-Activated Protein Kinase; Docetaxel; Drug Resistance, Neoplasm; Etoposide; Humans; Male; Morpholines; Prostatic Neoplasms; Protein Kinase Inhibitors; Pyridazines; Quinazolines; Taxoids

Targeted drug delivery for cancer therapy is an emerging area of research. Cancer cells overexpress certain biomarkers that can be exploited for their targeted therapy. Cyclic cell-penetrating peptides (cCPP) are increasingly assessed for intracellular cargo delivery in cancer cells. In this study, we have conjugated cabazitaxel (CBT) to the cCPP via an ester bond to assist CBT release in the tumor's acidic environment. Integrin targeting (RGDC, TP1) and extra domain B of fibronectin (EDB-Fn) targeting (CTVRTSAD, TP2) peptides were linked to the peptide-drug conjugate (cCPP-CBT) via a disulfide bond to provide targeting ability to the conjugates until they reach the tumor site. Conjugate

Topics: Amino Acid Sequence; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell-Penetrating Peptides; Drug Delivery Systems; Female; HEK293 Cells; Humans; Male; Molecular Structure; Prostatic Neoplasms; Taxoids

Traditional approaches used for transforming hydrophobic anticancer drugs into therapeutically available nanoparticles heavily rely on the noncovalent formulation of drugs within amphiphilic copolymers. However, these nanotherapies have not yet shown the expected favorable clinical outcomes in cancer patients, presumably due to their insufficient stability. To solve this dilemma, we conceive a new class of nanotherapies assembled with polymeric prodrugs that maintain pharmacological activity while substantially alleviate the drug toxicity in animals. By exploiting methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (mPEG-PLA) as a promoiety, cabazitaxel is tethered to the terminus of the PLA fragment via a hydrolysable ester linkage. These conjugates recapitulate the self-assembly to produce colloidal stable nanotherapies. In a xenograft model of prostate cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable nanotherapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Humans; Hydrophobic and Hydrophilic Interactions; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Polyesters; Polyethylene Glycols; Polymers; Prodrugs; Prostatic Neoplasms; Taxoids

Taxane treatment may be a suitable therapeutic option for patients with castration-resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR-Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR-V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored.. Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm. Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1-CabR1 and 22Rv1-CabR2, both showed upregulation of the ATP-binding cassette sub-family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR-antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1-CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment.. Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR-V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti-androgens.

Topics: Androgen Antagonists; Androstenes; Animals; Antineoplastic Agents; Castration; Cell Line, Tumor; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Male; Mice; Prostatic Neoplasms; Protein Isoforms; Receptors, Androgen; Taxoids; Transcriptome; Xenograft Model Antitumor Assays

Topics: Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids

Topics: Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids

Topics: Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids

Topics: Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids

Prostate cancer (PC) is the most common type of newly diagnosed malignancy in men. Combined chemotherapy has been shown to be an effective strategy for the treatment of PC therapy. Lipid-polymer hybrid nanoparticles (LPNs) are core-shell nanoparticles composed of a polymer core and a lipid shell, which are reported to provide significant advantages for combined PC therapy. This study synthesized an aptamer conjugated ligand and designed an aptamer-functionalized, curcumin (CUR) and cabazitaxel (CTX) co-delivered LPNs (APT-CUR/CTX-LPNs). APT-CUR/CTX-LPNs had a mean size of 121.3 ± 4.2 nm and a positive surface charge (23.5 ± 2.6 mV). Both CUR and CTX were sustained released from LPNs. Aptamer-functionalized APT-CUR/CTX-LPNs exhibited good cell inhibition ability, high tumor accumulation, and remarkable tumor inhibition efficiency at the drug ratio of 2:5 (CUR:CTX). The novel LPNs offers great promise for the double drugs delivery to the prostate cancer cells and tumor xenograft in vivo, showing the potential of synergistic combination therapy for prostate cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aptamers, Nucleotide; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Humans; Lipids; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Polymers; Prostatic Neoplasms; Taxoids; Xenograft Model Antitumor Assays

Despite widespread use of taxanes, mechanisms of action and resistance in vivo remain to be established, and there is no way of predicting who will respond to therapy. This study examined prostate cancer (PCa) xenografts and patient samples to identify in vivo mechanisms of taxane action and resistance. Docetaxel drug-target engagement was assessed by confocal anti-tubulin immunofluorescence to quantify microtubule bundling in interphase cells and aberrant mitoses. Tumor biopsies from metastatic PCa patients obtained 2 to 5 days after their first dose of docetaxel or cabazitaxel were processed to assess microtubule bundling, which correlated with clinical response. Microtubule bundling was evident in PCa xenografts 2 to 3 days after docetaxel treatment but was decreased or lost with acquired resistance. Biopsies after treatment with leuprolide plus docetaxel showed extensive microtubule bundling as did biopsies obtained 2 to 3 days after initiation of docetaxel or cabazitaxel in 2 patients with castration-resistant PCa with clinical responses. In contrast, microtubule bundling in biopsies 2 to 3 days after the first dose of docetaxel was markedly lower in 4 nonresponding patients. These findings indicate that taxanes target both mitotic and interphase cells in vivo and that resistance is through mechanisms that impair drug-target engagement. Moreover, the findings suggest that microtubule bundling after initial taxane treatment may be a predictive biomarker for clinical response.

Topics: Animals; Bridged-Ring Compounds; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Mice; Mice, Nude; Microtubules; Prostatic Neoplasms; Taxoids

Despite new drugs, metastatic prostate cancer remains fatal. Growing interest in the latest approved cabazitaxel taxane drug has markedly increased due to the survival benefits conferred when used at an earlier stage of the disease, its promising new therapeutic combination and formulation, and its differential toxicity. Still cabazitaxel's mechanisms of resistance are poorly characterized. The goal of this study was thus to generate a new model of acquired resistance against cabazitaxel in order to unravel cabazitaxel's resistance mechanisms.. Du145 cells were cultured with increasing concentrations of cabazitaxel, docetaxel/ taxane control or placebo/age-matched control. Once resistance was reached, Epithelial-to-Mesenchymal Translation (EMT) was tested by cell morphology, cell migration, and E/M markers expression profile. Cell transcriptomics were determined by RNA sequencing; related pathways were identified using IPA, PANTHER or KEGG software. The Wnt pathway was analyzed by western blotting, pharmacological and knock-down studies.. While age-matched Du145 cells were sensitive to both taxane drugs, docetaxel-resistant cells were only resistant to docetaxel and cabazitaxel-resistant cells showed a partial cross-resistance to both drugs concomitant to EMT. Using RNA-sequencing, the Wnt non-canonical pathway was identified as exclusively activated in cabazitaxel resistant cells while the Wnt canonical pathway was restricted to docetaxel-resistant cells. Cabazitaxel-resistant cells showed a minimal crossover in the Wnt-pathway-related genes linked to docetaxel resistance validating our unique model of acquired resistance to cabazitaxel. Pharmacological and western blot studies confirmed these findings and suggest the implication of the Tyrosine kinase Ror2 receptor in cabazitaxel resistant cells. Variation in Ror2 expression level altered the sensitivity of prostate cancer cells to both drugs identifying a possible new target for taxane resistance.. Our study represents the first demonstration that while Wnt pathway seems to play an important role in taxanes resistance, Wnt effectors responsible for taxane specificity remain un-identified prompting the need for more studies.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Down-Regulation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Humans; Male; Prostatic Neoplasms; Receptor Tyrosine Kinase-like Orphan Receptors; Taxoids; Transcriptome; Up-Regulation; Wnt Signaling Pathway

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

Cabazitaxel, a novel tubulin inhibitor with poor affinity for P-glycoprotein, is a second-generation taxane holding great promise for the treatment of metastatic castration-resistant prostate cancer. However, its poor solubility and lack of target-ability limit its therapeutic applications. Herein, we develop a biodegradable, enzyme-responsive, and targeted polymeric micelle for cabazitaxel. The micelle is formed from two amphiphilic block copolymers. The first block copolymer consists of PEG, an enzyme-responsive peptide, and cholesterol; whereas the second block copolymer consists of a targeting ligand, PEG and cholesterol. The enzyme-responsive peptide is cleavable in the presence of matrixmetaloproteinase-2 (MMP-2), which is overexpressed in the tumor microenvironment of prostate cancer. The micelle showed a very low critical micelle concentration (CMC), high drug loading, and high entrapment efficiency. Release of cabazitaxel from the micelle is dependent on the cleavage of the enzyme-responsive peptide. Moreover, the micelle showed dramatically higher cellular uptake in prostate cancer cells compared to free cabazitaxel. Importantly, the ligand-coupled polymeric micelle demonstrated better inhibition of tumor growth in mice bearing prostate cancer xenografts compared to unmodified micelle and free cabazitaxel. Taken together, these findings suggest that the enzyme-responsive cabazitaxel micelle is a potent and promising drug delivery system for advanced prostate cancer therapy. STATEMENT OF SIGNIFICANCE: Herein, we develop a biodegradable, enzyme-responsive, and actively targeted polymer micelle for cabazitaxel, which is a novel tubulin inhibitor with poor affinity for P-glycoprotein. Despite cabazitaxel's great promise for metastatic castration-resistant prostate cancer, its poor solubility, lack of target-ability, and high systemic toxicity limit its therapeutic applications, and therefore a targeted delivery system is highly needed for cabazitaxel. Our results demonstrate the importance of active targeting in targeted prostate cancer therapy. Encapsulating cabazitaxel in the micelle increases its activity and is expected to reduce its systemic toxicity, which is a major hurdle in its clinical applications. Moreover, the polymeric micelle may servers as a promising nanoscale platform for the targeted delivery of other chemotherapeutic agents to prostate cancer.

Topics: Animals; Cell Line, Tumor; Humans; Male; Mice; Micelles; Polymers; Prostatic Neoplasms; Taxoids; Tumor Microenvironment

Cabazitaxel (CBZ) is a new taxane-based antitumor drug approved by the FDA for the treatment of prostate cancer, especially for patients with advanced prostate cancer for whom docetaxel is ineffective or causes aggravation. However, Tween 80 injection can cause serious allergic reactions, and CBZ itself has strong toxicity, adverse reactions, and poor tumor selectivity, which greatly limits its clinical applications. Therefore, the CBZ-loaded bovine serum albumin nanoparticles (CBZ-BSA-Gd-NPs) were developed to overcome the allergenic response of Tween 80 and realize the integration of diagnosis and treatment.. CBZ-BSA-Gd-NPs were prepared by the biomineralization method. The characterization, magnetic resonance imaging (MRI), safety, and antitumor activity of the nanoparticles were evaluated in vitro and in vivo.. The prepared nanoparticles were uniform in size (166 nm), with good MRI performance and stability over 24 h. Compared with CBZ-Tween 80 injection, CBZ-BSA-Gd-NPs showed much lower hemolysis, similar tumor inhibition, and enhanced cellular uptake in vitro. The pharmacokinetic behavior of CBZ-BSA-Gd-NPs in rats showed that the retention time of the nanoparticles was prolonged, the clearance rate decreased, and the area under the drug-time curve increased. The distribution of CBZ-BSA-Gd-NPs in nude mice was characterized by UPLC-MS/MS and MRI, and the results showed that CBZ-BSA-Gd-NPs could effectively target tumor tissues with reduced distribution in the heart, liver, spleen, lungs, and kidneys compared with CBZ-Tween 80, which indicated that CBZ-BSA-Gd-NPs not only had a passive targeting effect on tumor tissue but also achieved the integration of diagnosis and treatment. In vivo, CBZ-BSA-Gd-NPs showed improved tumor inhibitory effect with a safer profile.. In summary, CBZ-BSA-Gd-NPs can serve as an effective therapeutic drug carrier to deliver CBZ into prostate cancer, and realize the integration of diagnosis and therapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chromatography, Liquid; Contrast Media; Docetaxel; Drug Carriers; Humans; Magnetic Resonance Imaging; Male; Mice, Inbred BALB C; Nanoparticles; Prostatic Neoplasms; Rats, Sprague-Dawley; Serum Albumin, Bovine; Tandem Mass Spectrometry; Taxoids; Tissue Distribution

For patients with metastatic prostate cancer, the 5-year survival rate of 31% points to a need for novel therapies and improvement of existing modalities. We propose that p53 gene therapy and chemotherapy, when combined, will provide superior tumor cell killing for the treatment of prostate carcinoma. To this end, we have developed the AdRGD-PGp53 vector which offers autoregulated expression of p53, resulting in enhanced tumor cell killing in vitro and in vivo. Here, we combined AdRGD-PGp53 along with the chemotherapy drugs used in the clinical treatment of prostate carcinoma, mitoxantrone, docetaxel, or cabazitaxel. Our results indicate that all drugs increase phosphorylation of p53, leading to improved induction of p53 targets. In vitro experiments reveal that AdRGD-PGp53 sensitizes prostate cancer cells to each of the drugs tested, conferring increased levels of cell death. In a xenograft mouse model of in situ gene therapy, AdRGD-PGp53 treatment, when combined with cabazitaxel, drastically reduced tumor progression and increased survival rates to 100%. Strikingly, we used a sub-therapeutic dose of cabazitaxel thus avoiding leukopenia, yet still showed potent anti-tumor effects when combined with AdRGD-PGp53 in this mouse model. The AdRGD-PGp53 approach warrants further development for its application in gene therapy of prostate carcinoma.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Disease-Free Survival; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Genes, p53; Genetic Therapy; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Prostate; Prostatic Neoplasms; Taxoids; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.

Topics: Antineoplastic Agents; Cell Line, Tumor; Chromones; Docetaxel; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gene Knockdown Techniques; Humans; Male; Morpholines; Prostatic Neoplasms; Protein Binding; PTEN Phosphohydrolase; Taxoids; Tubulin

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

Herein, ferumoxytol (Fer) capped antiprogrammed cell death-ligand 1 (PD-L1) antibodies (aPD-L1) loaded ultralarge pore mesoporous silica nanoparticles (Fer-ICB-UPMSNPs) are formulated for a sequential magnetic resonance (MR) image guided local immunotherapy after cabazitaxel (Cbz) chemotherapy for the treatment of prostate cancer (PC). The highly porous framework of UPMSNP provides a large capacity for aPD-L1. Fer capping of the pores extends the period of aPD-L1 release and provides MR visibility of the aPD-L1 loaded UPMSNP. As-chosen Cbz chemotherapy prior to the local immunotherapy induces strong immunogenic cell death, dendritic cell maturation, and upregulation of PD-L1 of tumor cells. Finally, tumor growth inhibition of sequential MR image-guided local delivery of Fer-ICB-UPMSNPs and a tumor specific adoptive immune reaction are demonstrated in the pretreated Tramp C1 PC mouse model with Cbz chemotherapy. The tumor suppression is superior to those obtained with systemic ICB treatment after Cbz, only Fer-ICB-UPMSNP or only Cbz. As a proof-of concept, MR image-guided local ICB immunotherapy using Fer-ICB-UPMSNPs after chemotherapy suggests a new perspective of translational local immunotherapy for patients who are treated with standard chemotherapies.

Topics: Animals; Cell Proliferation; Ferrosoferric Oxide; Flow Cytometry; Humans; Immunohistochemistry; Immunotherapy; Magnetic Resonance Imaging; Male; Mice; Microscopy, Electron, Scanning; Porosity; Prostatic Neoplasms; Silicon Dioxide; Taxoids

Latent tuberculosis infection (LTBI) describes the dormant state of tuberculosis (TB), in which persistent immune-related interaction between TB and T-cells maintain its state. Cabazitaxel (CBZ) is reported to improve overall survival in patients with castration-resistant prostate cancer (CRPC) after progression observed in regimens including docetaxel. CBZ is known for severe myelosuppression; however there is no recommendation for the treatment of LTBI before CBZ treatment. To the authors' knowledge, this is the first report to describe reactivation of LTBI induced by CBZ.. A 75-year-old Japanese male with a medical history of TB since 16 years of age had been treated for prostate cancer (PC) (initial prostate-specific antigen 532 ng/ml; cT4N1M1b; Gleason score4+4) with androgen deprivation therapy, abiraterone, and docetaxel. Calcified nodules and radiological findings of LTBI were present in the upper right lobe since the diagnosis of PC. After progression was observed during these treatments, CBZ was administered combined with pegfilgrastim, long-acting granulocyte colony-stimulating factor (G-CSF). Seven days after the third course of CBZ, he was admitted to the authors' hospital to treat febrile neutropenia (FN). High fever persisted even after myelosuppression had recovered. Computed tomography (CT) revealed distribution of small nodules in the bilateral lungs, for which miliary TB was included in the differential diagnosis. T-Spot, interferon-gamma-release assay, and bronchoscopy yielded no significant findings; however, sputum and urine culture confirmed the diagnosis of TB.. CT, sputum and urine culture confirmed the diagnosis of miliary TB.. The patient was treated with anti-bacterial therapy (cefepime) on hospital admission, which was not effective. After the diagnosis of miliary TB was confirmed, anti-TB drugs, including isoniazid, rifampicin, pyrazinamide and ethambutol, were administered.. Despite anti-TB therapy, high fever persisted and radiological findings worsened. Fifty days after the third course of CBZ, the patient died of respiratory dysfunction caused by progression of miliary TB.. Management of LTBI is needed in cases of radiographic findings of LTBI and medical history of TB before CBZ treatment, despite the rarity of LTBI reactivation in patients with PC.

Topics: Aged; Antitubercular Agents; Fatal Outcome; Humans; Latent Tuberculosis; Male; Prostatic Neoplasms; Taxoids; Tuberculosis, Miliary

Topics: Androstenes; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids

Understanding the mechanism of chemoresistance and disease progression in patients with prostate cancer is important for developing novel treatment strategies. In particular, developing resistance to cabazitaxel is a major challenge in patients with docetaxel-resistant and castration-resistant prostate cancer (CRPC) because cabazitaxel is often administered as a last resort. However, the mechanism by which cabazitaxel resistance develops is still unclear. C-C motif chemokine ligands (CCL) were shown to contribute to the castration resistance of prostate cancer cells via an autocrine mechanism. Therefore, we focused on CCL as key factors of chemoresistance in prostate cancer cells. We previously established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR. cDNA microarray analysis revealed that the expression of CCL2 was upregulated in both DU145-TxR and DU145-TxR/CxR cells compared with DU145 cells. The secreted CCL2 protein level in DU145-TxR and DU145-TxR/CxR cells was also higher than in parental DU145 cells. The stimulation of DU145 cells with CCL2 increased the proliferation rate under treatments with cabazitaxel, and a CCR2 (a specific receptor of CCL2) antagonist suppressed the proliferation of DU145-TxR and DU145-TxR/CxR cells under treatments of cabazitaxel. The CCL2-CCR2 axis decreased apoptosis through the inhibition of caspase-3 and poly(ADP-ribose) polymerase (PARP). CCL2 is apparently a key contributor to cabazitaxel resistance in prostate cancer cells. Inhibition of the CCL2-CCR2 axis may be a potential therapeutic strategy against chemoresistant CRPC in combination with cabazitaxel.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Chemokine CCL2; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Mice, SCID; Prostatic Neoplasms; Receptors, CCR2; Taxoids; Tumor Burden; Xenograft Model Antitumor Assays

Cabazitaxel, a semi-synthetic taxane of the third generation, inhibits prostate cancer (PC) cell growth by affecting the microtubule architecture. Since cabazitaxel has also been demonstrated to inhibit androgen receptor (AR) functionality, AR and AR-associated heat shock protein (HSP) expressions in the presence of cabazitaxel were characterized.. AR and HSP expressions were assessed via Western blotting utilizing a PC-cell-line in vitro system incubated with cabazitaxel.. Incubation experiments with 0.3 nM cabazitaxel exhibited significantly reduced levels of AR and the AR-associated factors HSP90α, HSP40, and HSP70/HSP90 organising protein. Furthermore, expression of the anti-apoptotic factor HSP60 was suppressed. In contrast to other anticancer compounds, cabazitaxel did not alter the cytoprotective chemoresistance factor HSP27.. Despite the deregulation of microtubule organisation, cabazitaxel has been shown to suppress the expression of HSP. Very notably, and may be as a result of down-regulated HSP, cabazitaxel additionally inhibits the expression of the AR in AR-positive PC cells. Thus, cabazitaxel bears an additional anti-proliferative activity which is at least in part specific for PC cells.

Topics: Androgen Receptor Antagonists; Cell Proliferation; Heat-Shock Proteins; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Taxoids; Tumor Cells, Cultured

Inactivation of the androgen receptor (AR) pathway by androgen deprivation therapy (ADT) is the mainstay of (metastatic) prostate cancer therapy. Ultimately, the AR pathway will be re-activated despite castrate levels of circulating androgens. Thereby, maintaining its role even in castration resistant prostate cancer (CRPC). The recent STAMPEDE and CHAARTED trials showed that docetaxel in combination with ADT increased survival in hormone sensitive prostate cancer patients, suggesting cross-talk between AR signaling and chemotherapy efficacy. We hypothesized that a similar interaction may also apply for CRPC that is treated with cabazitaxel. We studied the impact of androgen status on the efficacy, pharmacodynamics and -kinetics of cabazitaxel in a unique and clinically relevant patient derived xenograft model of castration resistant disease. We found that cabazitaxel is highly effective in a castrate setting with strongly reduced AR activation, while tumor growth inhibition by cabazitaxel was completely abolished in the presence of high AR pathway activity. Moreover, additional experiments showed that intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals. We confirmed that cabazitaxel pharmacokinetics were not affected by testosterone, suggesting that androgen status might influence cabazitaxel tumor uptake directly. This study reveals the impact of androgen status on cabazitaxel efficacy and supports the potential of combination of taxane chemotherapeutics with AR axis targeting agents.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Humans; Male; Mice, Nude; Prostatic Neoplasms; Taxoids; Testosterone; Treatment Outcome; Xenograft Model Antitumor Assays

Combining chemotherapeutics to treat malignant tumors has been shown to be effective in preventing drug resistance, tumor recurrence, and reducing tumor size. We modeled combination drug therapy in PC-3 human prostate cancer cells using mixture design response surface methodology (MDRSM), a statistical technique designed to optimize compositions that we applied in a novel manner to design combinations of chemotherapeutics. Conventional chemotherapeutics (mitoxantrone, cabazitaxel, and docetaxel) and natural bioactive compounds (resveratrol, piperlongumine, and flavopiridol) were used in 12 different combinations containing three drugs at varying concentrations. Cell viability and cell cycle data were collected and used to plot response surfaces in MDRSM that identified the most effective concentrations of each drug in combination. MDRSM allows for extrapolation of data from three or more compounds in variable ratio combinations, unlike the Chou-Talalay method. MDRSM combinations were compared with combination index data from the Chou-Talalay method and were found to coincide. We propose MDRSM as an effective tool in devising combination treatments that can improve treatment effectiveness and increase treatment personalization, because MDRSM measures effectiveness rather than synergism, potentiation, or antagonism.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dioxolanes; Docetaxel; Drug Synergism; Flavonoids; Humans; Male; Mitoxantrone; Models, Statistical; Piperidines; Prostatic Neoplasms; Resveratrol; Taxoids

Current treatments for castration resistant prostate cancer (CRPC) largely fall into two classes: androgen receptor (AR)-targeted therapies such as the next-generation antiandrogen therapies (NGAT), enzalutamide and abiraterone, and taxanes such as docetaxel and cabazitaxel. Despite improvements in outcomes, patients still succumb to the disease due to the development of resistance. Further complicating the situation is lack of a well-defined treatment sequence and potential for cross-resistance between therapies. We have developed several models representing CRPC with acquired therapeutic resistance. Here, we utilized these models to assess putative cross-resistance between treatments. We find that resistance to enzalutamide induces resistance to abiraterone and vice versa, but resistance to neither alters sensitivity to taxanes. Acquired resistance to docetaxel induces cross-resistance to cabazitaxel but not to enzalutamide or abiraterone. Correlating responses with known mechanisms of resistance indicates that AR variants are associated with resistance to NGATs, whereas the membrane efflux protein ABCB1 is associated with taxane resistance. Mechanistic studies show that AR variant-7 (AR-v7) is involved in NGAT resistance but not resistance to taxanes. Our findings suggest the existence of intra cross-resistance within a drug class (i.e., within NGATs or within taxanes), whereas inter cross-resistance between drug classes does not develop. Furthermore, our data suggest that resistance mechanisms differ between drug classes. These results may have clinical implications by showing that treatments of one class can be sequenced with those of another, but caution should be taken when sequencing similar classed drugs. In addition, the development and use of biomarkers indicating resistance will improve patient stratification for treatment.

Topics: Androgen Antagonists; Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Staging; Prostatic Neoplasms; Receptors, Androgen; Taxoids

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Animals; Antineoplastic Agents; Cyclobutanes; Disease Progression; Docetaxel; Down-Regulation; Humans; Male; Mice; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prostate; Prostatic Neoplasms; Receptors, Androgen; Taxoids; Transcriptional Regulator ERG

More than half of prostate cancer patients use, in addition to conventional therapies, some kind of complementary medicine, including flavonoid-rich products. However, knowledge about the co-effects of flavonoids with cytotoxic chemotherapies is still rather poor. Therefore, this study was undertaken to assess the cytotoxic activity of flavonoids and their interactions with taxanes in human advanced prostate cancer cells.. Cytotoxicity of different flavonoids and their effects on the efficacy of docetaxel and cabazitaxel were studied in the human metastatic prostate cancer cell line PPC-1, using MTT colorimetric assay.. Both taxanes suppressed the viability of PPC-1 cells with IC. Flavonoid hesperetin remarkably suppressed the cytotoxic efficacy of taxanes in prostate cancer cells. Therefore, caution is required from prostate cancer patients who take hesperetin-containing oral supplements.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Dietary Supplements; Docetaxel; Drug Antagonism; Hesperidin; Humans; Male; Prostatic Neoplasms; Taxoids

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

Topics: Antineoplastic Agents; Humans; Male; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids

Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC.

Topics: Androgen Antagonists; ATP Binding Cassette Transporter, Subfamily B; Bridged-Ring Compounds; Cell Line, Tumor; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Taxoids

The aim of this study was to develop a novel cabazitaxel bone targeted nanoparticle (NP) system for improved drug delivery to the bone microenvironment.. Nanoparticles were developed using poly(D,L-lactic-co-glycolic acid) and cabazitaxel as the core with amino-bisphosphonate surface conjugation. Optimization of nanoparticle physiochemical properties, in vitro evaluation in prostate cancer cell lines and in vivo testing in an intraosseous model of metastatic prostate cancer was performed.. This bone targeted cabazitaxel nanocarrier system showed significant reduction in tumor burden, while at the same time maintaining bone structure integrity and reducing pain in the mouse tumor limb.. This bone microenvironment targeted nanoparticle system and clinically relevant approach of evaluation represents a promising advancement for treating bone metastatic cancer.

Topics: Animals; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Cell Line, Tumor; Cell Survival; Diphosphonates; Drug Carriers; Drug Liberation; Humans; Lactic Acid; Male; Mice; Mice, Nude; Nanoparticles; Pain; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostatic Neoplasms; Surface Properties; Taxoids; Xenograft Model Antitumor Assays

Taxanes are routinely used to treat men with advanced prostate cancer, yet their molecular mode of action is poorly characterized. Taxanes stabilize microtubules and may hence interfere with a plethora of cellular processes, most notably mitosis. However, prostate cancer is typically a slowly growing tumor suggesting that additional processes play a role in the response to taxanes.. Here, we analyzed the potential effect of taxanes on microtubuli-dependent intracellular transport and signaling processes, specifically, nuclear translocation of the androgen receptor and modulation of the RAS-RAF-MEK-ERK signaling cascade.. We show that the androgen-driven nuclear translocation of the androgen receptor remains virtually undisturbed by docetaxel in prostate cancer cells. However, we found a striking down-regulation of activated ERK1/2 together with enhanced cytotoxicity in both docetaxel or cabazitaxel-treated cells that was comparable to direct MEK kinase inhibition. Remarkably, MEK inhibition alone was less effective in inducing cytotoxicity than taxanes indicating that a down-regulation of activated ERK1/2 may be necessary but is not sufficient for taxane-induced antitumoral effects. In line with this notion, we show in a xenograft mouse model that prostate cancer cells that are resistant to docetaxel overexpress activated ERK1/2. Taken together, our findings underscore that the modulation of ERK1/2 activation, in concert with other mechanisms, plays an important role in taxane-induced antineoplastic effects on prostate cancer cells.. These results suggest at least partially nonoverlapping effects of docetaxel and androgen deprivation therapy and hence help to understand recent clinical findings. A further elucidation of the mode of action of docetaxel would have important implications to optimize current treatment strategies and biomarker development for men with metastatic prostate cancer.

Topics: Animals; Antineoplastic Agents; Biological Transport; Cell Line, Tumor; Docetaxel; Down-Regulation; Drug Resistance, Neoplasm; Humans; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Prostatic Neoplasms; Protein Translocation Systems; Proto-Oncogene Proteins p21(ras); raf Kinases; Receptors, Androgen; Taxoids; Xenograft Model Antitumor Assays

Penile metastases are extremely rare events and generally occurs at a late stage of primary disease. They mostlyoriginate from prostate and bladder in the genitourinary tract. Penile metastases have a dismal prognosis and verylow survival rates. We report a case of penile metastasis in 70-year-old geriatric male patient with prostatic adenocarcinomawho was treated with cabazitaxel chemotherapy beyond 20 cycles with a good response and acceptableminimal toxicity.

Topics: Adenocarcinoma; Aged; Humans; Male; Penile Neoplasms; Prostatic Neoplasms; Remission Induction; Taxoids

Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the β-radiation emitted by. The cytotoxic effects of single and combined treatment with taxanes and. The survival curves showed dose-dependent cell growth inhibition for both the taxanes and. This proof-of-mechanism study exploring radiosensitization by combining

Topics: Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Chemoradiotherapy; Chemotherapy, Adjuvant; DNA Repair; Docetaxel; Dose-Response Relationship, Drug; Etidronic Acid; Humans; Male; Organometallic Compounds; Prostatic Neoplasms; Radiation-Sensitizing Agents; Radiopharmaceuticals; Taxoids

Cabazitaxel is an approved second-line treatment for docetaxel-refractory metastatic castration-resistant prostate cancer. However, the median time to progression on cabazitaxel is 2.8 months. We aimed to determine whether DNA methylation plays a role in cabazitaxel resistance.. DU145 cells, resistant to docetaxel and cabaxitaxel (DU145 10DRCR), were generated from cells resistant to 10 nM docetaxel (DU145 10DR). The effect of pre-treatment with 5-azacytidine was determined with regards to cabazitaxel sensitivity. Gene expression profiling was carried-out on DU145 10DR, DU145 10DRCR and DU145 10DRCR treated with 5-azacytidine.. Pre-treatment of cells with 5-azacytidine resulted in enhanced sensitivity to cabazitaxel. Gene expression profiling identified a subset of genes that may be regulated by DNA methylation.. Our results indicate that DNA methylation of pro-apoptotic and cell-cycle regulatory genes may contribute to cabazitaxel resistance and pre-treatment with 5-azacytidine may restore sensitivity to cabazitaxel in prostate cancer cells.

Topics: Antineoplastic Agents; Azacitidine; Cell Line, Tumor; Cell Survival; DNA Methylation; DNA Modification Methylases; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Inhibitors; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Taxoids; Time Factors

We studied the efficacy and safety of cabazitaxel in unselected real-life patients.. We retrospectively investigated all patients with metastatic prostate cancer (mPC) treated with cabazitaxel 25 mg/m2 i.v. every 3 weeks combined with oral prednisolone (10 mg once daily) after first-line docetaxel chemotherapy. Study issues were to report patient characteristics and cabazitaxel data in terms of tolerance and efficacy. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. All data were compared with TROPIC results.. From 2011 to 2014, 41 patients received cabazitaxel; 15 patients (37%) had a performance status (PS) ≥2 versus 7% (p < 0.0001) in TROPIC, and 38 patients (93%) presented a Gleason score ≥7 at baseline (vs. 60%; p < 0.0001). All patients had metastatic disease at baseline. Previous therapies were radiotherapy in 17 patients (41 vs. 61%; p = 0.01) and surgery in 24 patients (59 vs. 52%; p = 0.4). The median number of cabazitaxel cycles was 5 (1-10) versus 6 (3-10) in TROPIC. Five patients completed 10 cycles of cabazitaxel (12%) versus 28% in TROPIC (p = 0.03). Toxicities were anemia (12 patients, 29%), diarrhea (9 patients, 22%), nausea (7 patients, 17%), pain (6 patients, 15%), sepsis (4 patients, 10%), neutropenia (3 patients, 7%) and urinary tract infection (1 patient, 2%). The tumor response rate was 19.5 versus 14.4% in TROPIC (nonsignificant). PFS was 4.5 months (95% CI 3.3-6.4) in our analysis and 2.8 months (95% CI 2.4-3.0) in TROPIC. OS was 12.1 months (95% CI 9.2 to not reached) and 15.1 months (95% CI 14.1-16.3), respectively.. In our unselected mPC patients with poorer baseline clinical conditions and aggressive disease, cabazitaxel seems efficient and not more toxic than in the TROPIC study.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Evidence-Based Medicine; Humans; Kaplan-Meier Estimate; Male; Neoplasm Metastasis; Prednisolone; Prostatic Neoplasms; Retrospective Studies; Survival Rate; Taxoids; Treatment Outcome

We report the synthesis of an amphiphilic triblock copolymer composed of a hydrophilic poly(ethylene glycol) (PEG) block, a central poly(acrylic acid) (PAA) block, and a hydrophobic poly(methyl methacrylate) (PMMA) block using atom transfer radical polymerization technique. We examined the self-assembly of PEG-b-PAA-b-PMMA copolymers in aqueous solutions forming nanosized micelles and their ability to encapsulate hydrophobic guest molecules such as Nile Red (NR) dye and cabazitaxel (CTX, an anticancer drug). We used 2,2β'-(propane-2,2-diylbis(oxy))-diethanamine to react with the carboxylic acid groups of the central PAA block forming acid-labile, shell cross-linked micelles (SCLM). We investigated the loading efficiency and release of different guest molecules from non-cross-linked micelles (NSCLM) and shell cross-linked micelles (SCLM) prepared by reacting 50% (SCLM-50) and 100% (SCLM-100) of the carboxylic acid groups in the PAA in physiologic (pH 7.4) and acidic (pH 5.0) buffer solutions as a function of time. We examined the uptake of NR-loaded NSCLM, SCLM-50, and SCLM-100 micelles into PC-3 and C4-2B prostate cancer cells and the effect of different micelle compositions on membrane fluidity of both cell lines. We also investigated the effect of CTX-loaded NSCLM, SCLM-50, and SCLM-100 micelles on the viability of PC-3 and C4-2B cancer cells compared to free CTX as a function of drug concentration. Results show that PEG-b-PAA-b-PMMA polymers form micelles at concentrations ≥11 μg/mL with an average size of 40-50 nm. CTX was encapsulated in PEG-b-PAA-b-PMMA micelles with 55% loading efficiency in NSCLM. In vitro release studies showed that 30% and 85% of the loaded CTX was released from SCLM-50 micelles in physiologic (pH 7.4) and acidic (pH 5.0) buffer solutions over 30 h, confirming micelles' sensitivity to solution pH. Results show uptake of NSCLM and SCLM into prostate cancer cells delivering their chemotherapeutic cargo, which triggered efficient cancer cell death. PEG-b-PAA-b-PMMA micelles were not hemolytic and did not cause platelet aggregation, which indicate their biocompatibility.

Topics: Cell Line; Cell Line, Tumor; Cells, Cultured; Humans; Hydrogen-Ion Concentration; Macrophages; Male; Micelles; Prostatic Neoplasms; Taxoids

Topics: Antineoplastic Agents; Docetaxel; Humans; Male; Prostatic Neoplasms; Taxoids

Cabazitaxelis a taxane-type antineoplastic agent used for treating prostate cancer. Although typical side effects include neutropenia and fatigue, no studies have investigated eye disorders as a possible side effect, and the details are not clear. Herein, we report our experience of an undeniable case of optic neuropathy caused by cabazitaxel. A 78-year-old man had been diagnosed with prostate cancer (cT3aN1M1b, stage IV) 3 years previously, with a treatment history of bicalutamide, leuprorelin, flutamide, docetaxel, abiraterone, and enzalutamide. Because of a decline in vision during the second and third administration cycles of cabazitaxel, the patient visited an ophthalmologist. He was found to have reduced visual acuity, reduced central critical flicker frequency, narrowed field of vision, and impaired color vision, and was diagnosed with optic neuropathy. Although cabazitaxel administration was continued through 6 cycles, the symptoms were unchanged, and no drastic exacerbation was seen. This patient undeniably developed optic neuropathy due to cabazitaxel. Optic neuropathy due to taxane-type antineoplastic agents has also been reported with paclitaxel or docetaxel, and all precautions should be taken when administering such drugs. Detailed studies that include data from a larger number of facilities should be conducted in the future.

Topics: Aged; Humans; Male; Neoplasm Staging; Optic Nerve Diseases; Prostatic Neoplasms; Taxoids

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

Topics: Adenocarcinoma; Androgens; Androstenes; Animals; Antineoplastic Agents, Phytogenic; Benzamides; Biological Transport; Cell Line, Tumor; Docetaxel; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Heterografts; Humans; Male; Mice, Nude; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Nitriles; Organic Anion Transporters, Sodium-Independent; Phenylthiohydantoin; Prostatic Neoplasms; RNA Interference; RNA, Small Interfering; Solute Carrier Organic Anion Transporter Family Member 1B3; Taxoids

Cabazitaxel-loaded human serum albumin nanoparticles (Cbz-NPs) were synthesized to overcome vehicle-related toxicity of current clinical formulation of the drug based on Tween-80 (Cbz-Tween). A salting-out method was used for NP synthesis that avoids the use of chlorinated organic solvent and is simpler compared to the methods based on emulsion-solvent evaporation. Cbz-NPs had a narrow particle size distribution, suitable drug loading content (4.9%), and superior blood biocompatibility based on in vitro hemolysis assay. Blood circulation, tumor uptake, and antitumor activity of Cbz-NPs were assessed in prostatic cancer xenograft-bearing nude mice. Cbz-NPs exhibited prolonged blood circulation and greater accumulation of Cbz in tumors along with reduced toxicity compared to Cbz-Tween. Moreover, hematoxylin and eosin histopathological staining of organs revealed consistent results. The levels of blood urea nitrogen and serum creatinine in drug-treated mice showed that Cbz-NPs were less toxic than Cbz-Tween to the kidneys. In conclusion, Cbz-NPs provide a promising therapeutic for prostate cancer.

Topics: Animals; Antineoplastic Agents; Blood Urea Nitrogen; Creatinine; Drug Carriers; Humans; Male; Mice, Nude; Nanoparticles; Particle Size; Prostatic Neoplasms; Serum Albumin; Taxoids; Tissue Distribution; Xenograft Model Antitumor Assays

Paclitaxel (PTX) is a microtubule-targeting drug widely used for the treatment of a variety of cancers. However, drug resistance can emerge after a series of treatments, and this can seriously affect the patient's prognosis. Here, we analyzed the mechanism of PTX resistance using a human prostate cancer cell line, PC3, and its PTX-resistant subline, PC3-PR. Compared with PC3, PC3-PR exhibited some unique phenotypes that might be associated with PTX resistance, including decreased expression of acetylated α-tubulin and the cell cycle regulator p21, and increased expression of βIII tubulin, histone deacetylase 6 (HDAC6), and the anti-apoptotic protein Bcl2. The drug exporters MDR1 and MRP1 were not involved in PTX resistance. Although cabazitaxel (CTX), a novel taxoid, has been reported to overcome PTX resistance, its mechanism of action is unknown. We found that treatment of PC3-PR cells with CTX induced expression of acetylated α-tubulin and p21, but not the related regulators p27, p15, and p16 or the Bcl2 family proteins. The pan-HDAC inhibitors trichostatin A and suberanilohydroxamic acid and the HDAC6-specific inhibitor tubacin inhibited PC3-PR proliferation and increased expression of p21 and acetylated α-tubulin in a manner similar to CTX. Our data shed light on the cellular response to PTX and CTX.

Topics: Acetylation; Anilides; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Male; Paclitaxel; Prostatic Neoplasms; Protein Stability; Taxoids; Tubulin; Tubulin Modulators; Vorinostat

Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863-74. ©2016 AACR.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Flavonoids; Flavonols; Humans; Male; Mice; Mice, Nude; Neoplastic Stem Cells; Prostatic Neoplasms; Taxoids; Treatment Outcome; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

The objective of the present study is to determine whether uptake of [(18)F]fluoromethylcholine ([(18)F]FCH) in comparison with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) accurately reflects chemotherapy efficacy at the tumor cell level in prostate cancer (PC).. The effects of docetaxel and cabazitaxel on viable tumor cell number were explored in four PC cell lines. Cellular uptake of [(18)F]FDG and [(18)F]FCH was compared with the effects measured using sulforhodamine B (SRB) assay, cell counting and colony formation assay (CFA), as proximators of viable tumor cell number. Agreement between uptake and cell numbers was assessed by Bland-Altman plots.. [(18)F]FCH uptake in all PC cell lines significantly correlated to the cell numbers surviving the respective drug concentrations. Bland-Altman analysis showed that [(18)F]FDG uptake resulted in signal overestimation and higher variability after chemotherapy.. [(18)F]FCH uptake correlates well with viable tumor cell numbers remaining after docetaxel and cabazitaxel exposure. Radiolabeled choline is a potential response monitoring biomarker after chemotherapy for PC.

Topics: Antineoplastic Agents; Cell Line, Tumor; Choline; Docetaxel; Drug Screening Assays, Antitumor; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Humans; Inhibitory Concentration 50; Male; Prostatic Neoplasms; Radionuclide Imaging; Radiopharmaceuticals; Rhodamines; Taxoids

The development of a drug-resistant phenotype is the major challenge during treatment of castration-resistant prostate cancer (PC). In solid cancer entities, one of the major contributors to chemoresistance is the multidrug resistance 1 (MDR1) protein. Believed to be involved in the induction of MDR1 expression is the presence of anticancer drugs as well as the Y box binding protein 1 (YB-1).. Basal as well as drug-induced expression of MDR1 in established PC cell lines was assessed by Western blotting and mass spectrometry. Subsequently, the influence of YB-1 on MDR1 expression was examined via transient overexpression of YB-1.. While LNCaP and PC-3 cells showed no detectable amounts of MDR1, the resistance factor was found to be expressed in 22Rv1 cells. Despite this difference, all three cell lines demonstrated similar growth behavior in the presence of the first-line chemotherapeutic agent docetaxel. Incubation of 22Rv1 cells with docetaxel, cabazitaxel, and abiraterone did not significantly alter MDR1 expression levels. Furthermore, overexpression of the MDR1 controlling factor YB-1 showed no impact on MDR1 expression levels.. MDR1 was detectable in the PC cell line 22Rv1. However, this study suggests that MDR1 is of less importance for drug resistance in PC cells than in other types of solid cancer. Furthermore, in contrast to YB-1 properties in other malignancies, MDR1 regulation through YB-1 seems to be unlikely.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Line, Tumor; Cell Survival; Chromatography, Liquid; Docetaxel; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Prostate; Prostatic Neoplasms; Tandem Mass Spectrometry; Taxoids; Y-Box-Binding Protein 1

We hypothesized that the adverse event (AE) profile of cabazitaxel with regard to alopecia, nail changes, neuropathy, and dysgeusia differs from docetaxel.. Prospectively collected data on treatment-emergent AEs (frequency and grade [G]) from clinical trial databases of docetaxel every 3 weeks (q3w) (in TAX327 and VENICE) and cabazitaxel q3w (in TROPIC) were analyzed.. The frequency of new or worsening AEs (all G and G3-4) for 1301 patients was significantly less for alopecia, nail changes, neuropathy, and dysgeusia for cabazitaxel compared with docetaxel.. Treatment with cabazitaxel might cause less alopecia, nail changes, neuropathy, and dysgeusia compared with docetaxel.

Topics: Alopecia; Clinical Trials as Topic; Docetaxel; Drug-Related Side Effects and Adverse Reactions; Dysgeusia; Humans; Male; Nail Diseases; Peripheral Nervous System Diseases; Prospective Studies; Prostatic Neoplasms; Retrospective Studies; Taxoids

The prognosis of patients with advanced prostate cancer has improved over the last few years. In addition to the new antihormonal treatment, chemotherapy with agents such as docetaxel and cabazitaxel has contributed to the improved prognosis. After the introduction of abiraterone and enzalutamide, conventional chemotherapy seemed to become less important but the discussion about the use of chemotherapy for hormone-sensitive prostate cancer has gained attention again. Combining docetaxel with conventional androgen deprivation therapy (ADT) improves survival compared to ADT alone. In addition, docetaxel and cabazitaxel now represent the standard for first and second line therapy in patients with castration-resistant prostate cancer.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Docetaxel; Drug Therapy; Evidence-Based Medicine; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Treatment Outcome

Topics: Androstenes; Androstenols; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Denosumab; Diphosphonates; Docetaxel; Drug Approval; Drugs, Investigational; Estramustine; Goserelin; Humans; Imidazoles; Male; Mitoxantrone; Nitriles; Oligopeptides; Phenylthiohydantoin; Prostatic Neoplasms; Radioisotopes; Radium; Taxoids; Tissue Extracts; United States; United States Food and Drug Administration; Zoledronic Acid

Topics: Aged; Antineoplastic Agents; Cystitis; Hematuria; Humans; Male; Middle Aged; Prostatic Neoplasms; Radiation Injuries; Radiotherapy; Taxoids

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

Docetaxel chemotherapy is a standard treatment for fit men with symptomatic castration-resistant prostate cancer. Unfortunately docetaxel resistant disease will systematically develop and second-line treatment may be appropriate. Until recently no standard treatment was approved in this setting and mitoxantrone was commonly used. Three new drugs have shown benefit in randomised phase 3 multicenter clinical trials published since 2010. Cabazitaxel, abiraterone and enzalutamide were shown to prolong overall survival of men with metastatic castration-resistant prostate cancer previously treated with chemotherapy. Although still modest these results were deemed clinically significant and led to the reimbursement of Jevtana (cabazitaxel) and Zytiga (abiraterone) in Belgium in 2012.

Topics: Androstenes; Androstenols; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials, Phase III as Topic; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Male; Multicenter Studies as Topic; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

This study aimed to identify predictive/prognostic factors in castration-resistant prostate cancer patients treated with cabazitaxel.. Patients were enrolled from March 2011 to December 2011 in an international expanded access program. In January 2012, when cabazitaxel became commercially available, a prospective study was initiated at University Federico II of Naples and at Rionero in Vulture Hospital.. Forty-seven patients were enrolled in this study. Patients received a median of nine cycles of cabazitaxel. Median progression-free survival was 7.0 months (95% CI: 5.7-8.0). Seventeen patients were still alive at the time of the analysis, with a median overall survival of 14 months (95% CI: 11-16). At multivariate analysis, a higher Gleason score (≥ 8) appeared to be associated with prolonged progression-free survival (hazard ratio: 0.36; 95% CI: 0.18-0.72); however, the higher Gleason score showed no statistical impact on overall survival.. We hypothesize that the Gleason score has the potential to be incorporated in the clinical decision-making process for definition of treatment strategy in docetaxel-pretreated castration-resistant prostate cancer patients. We encourage further experimentation in this setting.

Topics: Aged; Castration; Disease-Free Survival; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

Cabazitaxel (Jevtana) has been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, most patients progress and become chemoresistant, which remains a major challenge in the management of advanced PCa. In this study, we investigated whether genistein, an isoflavone abundant in soy products, could sensitize mCRPC cells to cabazitaxel treatment in experimental models.. The in vitro and in vivo effect of genistein in enhancing the response of mCRPC cells to cabazitaxel chemotherapy was evaluated in experimental models.. Genistein increases the expression of pro-apoptotic protein Bax, activates apoptotic signals, and enhances the response to cabazitaxel treatment in mCRPC cells. In a PC3-luciferase xenograft model, the combined treatment with genistein and cabazitaxel significantly retarded the growth of mCRPC when compared to vehicle control, cabazitaxel, or genistein. Tissue staining confirmed the in vivo effect of genistein on the induction of Bax and activation of apoptosis.. This study provided the first preclinical evidence supporting that genistein could be beneficial in improving cabazitaxel chemotherapy in mCRPC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Proliferation; Genistein; Humans; Male; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Prostate; Prostatic Neoplasms; Taxoids

To determine the impact of prophylaxis with granulocyte-colony stimulating growth factor (G-CSF) on the risk of febrile neutropenia in a cohort of patients enrolled at the University Federico II of Naples and treated with cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC). We carried out a retrospective review of prospectively collected data of patients enrolled at our institution in a compassionate-use programme with cabazitaxel, aimed at providing early access to the drug before its commercial availability in mCRPC patients. Besides baseline clinical and demographic characteristics, data on treatment efficacy and toxicity, as well as those on the use of G-CSF per patient per cycle were extracted. Progression-free survival and overall survival were calculated using the Kaplan-Meier method. Fisher's exact test was used to explore a relationship between a single event of grade 3 or more neutropenia or febrile neutropenia and previous use of G-CSF. Univariate analysis was carried out to evaluate predictors of grade 3 or more neutropenia and/or febrile neutropenia. Of 34 patients enrolled at our institution from December 2010 to December 2011, 32 had received at least one dose of cabazitaxel and were included in the analysis. Patients received a median of 10 cabazitaxel cycles. Grade 3 or more neutropenia was common, occurring in 64.5% of patients. Three patients (9.3%) developed febrile neutropenia. Twenty-seven patients received prophylaxis with G-CSF during at least one cycle using peg-filgrastim. The risk of grade 3 or more neutropenia and/or febrile neutropenia per patient and per cycle was seven times lower when G-CSF was used. Baseline neutrophil count of less than 4570/mm was the strongest predictor of grade 3 or more neutropenia and/or febrile neutropenia. No toxic death was reported. Only one patient discontinued cabazitaxel because of an adverse event. Our analysis suggests that prophylaxis with peg-filgrastim may considerably reduce the incidence of grade 3 or more neutropenia and, possibly, of febrile neutropenia in mCRPC patients treated with cabazitaxel. Further analyses involving a larger population are warranted to confirm our results.

Topics: Aged; Antineoplastic Agents; Disease-Free Survival; Fever; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Neutrophils; Polyethylene Glycols; Prostatic Neoplasms; Recombinant Proteins; Retrospective Studies; Survival Rate; Taxoids; Treatment Outcome

Cabazitaxel (Cbz) is an approved second-line treatment in metastatic castration-resistant prostate cancer (mCRPC) following docetaxel therapy with a significant survival benefit compared with mitoxantrone. However, grade 3/4 toxicities were reported in 82% of patients.. To report on the safety results of mCRPC patients treated within a compassionate-use programme in Germany.. A total of 111 patients with a mean age of 67.9 yr (range: 49-81 yr) and progressive mCRPC were included. Patients had received a mean number of 12.7 ± 10.8 cycles (range: 6-69 cycles) of docetaxel with a mean cumulative dose of 970.9 mg/m(2); mean time from last docetaxel application to progression was 6.95 mo (range: 2-54 mo). Of the patients, 31.5% progressed by prostate-specific antigen (PSA) increase only; the remainder had a combination of PSA increase and clinical progression.. Cbz at a dosage of 25mg/m(2) intravenously every 3 wk combined with 5mg of oral prednisone twice a day.. Treatment-associated toxicity was the primary study end point; progression-free and overall survival were secondary end points. A descriptive statistical analysis was performed.. Patients received a mean number of 6.5 ± 2.2 cycles of Cbz and a mean cumulative dose of 160.3 ± 51.5mg/m(2). Grade 3 and 4 treatment-emergent adverse events were recorded in 34 patients (30.6%) and 18 patients (16.2%), respectively. Grade 3/4 anaemia, neutropenia, and thrombocytopenia were reported in 4.5%, 7.2%, and 0.9% of the patients, respectively. Neutropenic fever was reported in 1.8% of the patients. Grade 3/4 gastrointestinal toxicity was identified in 4.5% of the patients. Three patients died because of Cbz-related toxicity. Granulocyte colony-stimulating growth factors were used in 17.1% of patients. The limitations are due to the nonrandomised nature of the trial.. Treatment with Cbz is tolerable and is associated with a low incidence of serious adverse events in a real-world patient population with CRPC. The outcome of serious adverse events can be minimised with proactive treatment management and conscientious monitoring.

Topics: Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Compassionate Use Trials; Disease-Free Survival; Docetaxel; Fever; Germany; Humans; Kallikreins; Male; Middle Aged; Neutropenia; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Thrombocytopenia; Treatment Failure; Treatment Outcome

Topics: Androstenes; Androstenols; Antineoplastic Agents; Benzamides; Clinical Trials as Topic; Drug Approval; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Tissue Extracts; United States

This study aimed to investigate cabazitaxel efficacy in a model for docetaxel-resistant prostate cancer cells and to evaluate the involvement of ATP-cassette binding protein 4 (ABCC4) with regard to multidrug resistance.. Docetaxel and cabazitaxel sensitivity was measured in PC3 and R3327-MATLyLu (MLL) cell lines, using the sulforhodamine B (SRB) assay. ABCC4 expression was examined by western blotting and its functional involvement in drug sensitivity by blocking with MK571 inhibitor.. The docetaxel-resistant MLL cells (4.5-fold compared to cabazitaxel; p<0.001) were shown to express high levels of ABCC4, while non-resistant PC3 cells had no detectable ABCC4 expression. Functional inhibition of ABCC4 in MLL cells resulted in a two-fold decrease in effective concentration of docetaxel and had no effect on toxicity of cabazitaxel.. Cabazitaxel showed an improved therapeutic efficacy over docetaxel in ABCC4-expressing prostate cancer cells. ABCC4 appears to be an important determinant of docetaxel resistance, since its inhibition almost completely reversed resistance.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Docetaxel; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; In Vitro Techniques; Male; Multidrug Resistance-Associated Proteins; Prostatic Neoplasms; Taxoids

Topics: Abiraterone Acetate; Androstadienes; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Cancer Vaccines; Denosumab; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Taxoids; Tissue Extracts

Chemotherapy for men with metastatic castration-resistant prostate cancer (CRPC) conferred no survival advantage until 2004 when docetaxel was shown to improve survival when compared with mitoxantrone, which was approved for palliation of symptomatic disease in 1996. Since then, clinical trials have concentrated on three main populations of patients with metastatic CRPC: those who are chemotherapy naïve and are asymptomatic or minimally symptomatic, those who need docetaxel therapy, and those who have received docetaxel previously and/or those with symptomatic disease. Over the last year, four Phase III therapeutic trials have met their primary endpoint of improved overall survival: sipuleucel-T in the pre-chemotherapy setting, cabazitaxel and abiraterone in the post-docetaxel setting, and radium-223 for those with symptomatic bone metastases who have received or are not suitable to receive docetaxel. In addition to these therapeutic trials, a Phase III head-to-head trial of denosumab compared to zoledronic acid showed that denosumab was superior to zoledronic acid in delaying or preventing skeletal related events. As a result, the treatment paradigm for metastatic CRPC is changing rapidly. This paper reviews the data from these five completed Phase III trials and places these new agents, as well as those in ongoing Phase III trials, in the context of the old treatment paradigm for metastatic CRPC and discusses some of the challenges ahead for determining optimal timing and sequencing of treatments for metastatic CRPC.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Denosumab; Diphosphonates; Docetaxel; Humans; Imidazoles; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts; Zoledronic Acid

Interactive case studies formed a key feature of the third annual Interactive Genitourinary Cancer Conference held in April/May 2011 in Budapest, Hungary. These cases were used to discuss the practical aspects of the management of metastatic castration-resistant prostate cancer (mCRPC). Particular emphasis was placed on audience participation with potential management options posed as interactive questions to the delegates. This paper summarises these case studies and the related discussion. Docetaxel is the standard first-line chemotherapeutic agent for patients with mCRPC and, until recently, second-line therapeutic options were limited. Results from the recently completed TROPIC trial showed a statistically and clinically significant improvement in overall survival with the microtubule inhibitor cabazitaxel compared with mitoxantrone. Cabazitaxel has been shown to be well tolerated and has been approved in Europe and the USA as second-line chemotherapy for mCRPC. Prognostic factors have a potential benefit in individualised patient management in mCRPC. Pretreatment prognostic factors, including PSA doubling time, pain, visceral metastases, anaemia and progression of osseous metastases, have been shown to predict survival outcomes and can be used to guide treatment strategies, including appropriate timing of chemotherapy.   Multiple treatment options and significant heterogeneity among patients with advanced prostate cancer necessitate multidisciplinary team management in addition to patient education, as part of a patient-centred approach. The development of second-line chemotherapeutic agents together with the use of prognostic factors and a patient-centred multidisciplinary team approach provide encouraging new management prospects for patients with mCRPC.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Congresses as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Male; Palliative Care; Patient-Centered Care; Prognosis; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Taxoids

At the third annual Interactive Genitourinary Cancer Conference, held in Budapest from 30 April to 1 May 2011, the latest developments in the management of patients with high-risk localised and metastatic prostate cancer were discussed. Prostate cancer is the most common cancer in Western men and, for advanced disease, no curative agents are available. For men with high-risk localised disease there is debate about the best treatment approaches, with both radical prostatectomy and radiation therapy shown to improve outcomes. These approaches have started to be augmented as new techniques and therapies are developed. For instance, radiation therapy combined with androgen deprivation therapy has been shown to be more efficacious than radiation therapy alone, and there may also be a role for adjuvant/neoadjuvant chemotherapy. Ultimately a multidisciplinary approach will most probably result in the best outcomes for patients. The use of androgen deprivation therapy in men with prostate cancer needs to be monitored carefully, given that it results in adverse alterations in several metabolic parameters and an increased risk of further coronary events in men with cardiovascular disease in some studies. Until recently there were limited options for the management of men with advanced prostate cancer, but new agents for use in the post-docetaxel setting have recently been approved. These are cabazitaxel and abiraterone acetate, which have both shown a significant survival benefit in patients who have progressed on docetaxel. Additional agents, for these patients and for patients at other stages of disease, are in the later stages of development. The development of new agents has been aided by a greater understanding of the molecular mechanisms of resistance to current therapies and the recognition of new pathophysiological pathways. As the number of available therapeutic options increases, it will become increasingly important to tailor treatments to the individual patient. This may require the development of novel biomarkers or the use of existing or new predictive tools based on prognostic factors. To ensure optimal patient care, early and continuous involvement of the multidisciplinary team will be required.

Topics: Abiraterone Acetate; Androgen Receptor Antagonists; Androstadienes; Cardiovascular Diseases; Chemotherapy, Adjuvant; Congresses as Topic; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prognosis; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Taxoids

First clinical experiences with abiraterone and cabazitaxel for the treatment of metastatic castration-resistant prostate cancer patients following docetaxel chemotherapy are reported.. We describe PSA response rates and disease control rates determined by imaging studies at 3 months as well as side effects in the daily routine. All patients were treated within the"compassionate use" programs of cabazitaxel and abiraterone or treated according to their inclusion and exclusion criteria at the "Technische Universität München".. Of 54 patients, 15 were treated with cabazitaxel and 39 with abiraterone. In patients treated with cabazitaxel, after 3 months of therapy the PSA reduction rate > 50% was 46.2%, the PSA progression rate was 15.4%, and the disease control rate was 83.3%. Main grade 3/4 hematotoxicities were neutropenia (40%) and anemia (20%). Febrile neutropenia was observed in 2 of 15 (13.3%) patients. Main non-hematological grade 3/4 toxicities were diarrhea (13.3%) and polyneuropathy (13.3%). In patients treated with abiraterone, after 3 months of therapy the PSA reduction rate >50% was 35.1%, the PSA progression rate was 46.0%, and the disease control rate was 47.1%. Main grade 3/4 hematotoxicities were anemia (5.1%) and thrombocytopenia (5.1%). Main non-hematological toxicities were fatigue (20.5%), sweating (17.9%), and constipation (10.3%).. Utilization of cabazitaxel and abiraterone in the daily routine show response rates comparable to their approval studies with acceptable side effects.

Topics: Aged; Androstenes; Androstenols; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Compassionate Use Trials; Disease Progression; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Orchiectomy; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids

What's known on the subject? and What does the study add? Treatment options in the UK for men with metastatic castration-resistant prostate cancer (mCRPC) have been limited, and there is no standard approach, particularly in the second-line setting. The absence of a standard approach is further confounded by the differing definitions and terminologies still used in clinical practice to describe this group of patients (e.g. androgen-independent prostate cancer, hormone refractory prostate cancer, CRPC). With multiple new treatment options emerging, it will be critical to identify key considerations in our decision-making process and to establish an optimum, standardized approach to treatment so that new therapies can be assimilated into an mCRPC treatment algorithm and our routine clinical practice. Most UK oncologists consider patients with advanced, symptomatic prostate cancer as eligible for chemotherapy, although a poor performance status, significant co-morbid factors, advancing age, and the presence of asymptomatic disease with slowly rising prostate-specific antigen levels would prevent chemotherapy use. The decision to retreat with chemotherapy is largely driven by prior response to first-line chemotherapy. Many UK oncologists feel that UK clinical practice is likely to change over the next 5 years, with abiraterone acetate, MDV3100 and cabazitaxel likely to have the most positive impacts in the treatment of mCRPC.. To evaluate the current management of patients with advanced prostate cancer by UK oncologists. To gain insights into the future role of emerging therapies.. A semi-structured questionnaire was issued by the British Uro-oncology Group to society members during a closed meeting in September 2010. Emerging therapies evaluated were: abiraterone acetate, aflibercept, bevacizumab, cabazitaxel, custirsen, MDV3100, sipuleucel-T and zibotentan.. Eighty of 98 (82%) surveys were completed. Responders had on average 189 new referrals, and treated 126 patients with advanced prostate cancer each year. Chemotherapy was used by 86% of responders for patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC), although poor performance status, advancing age and slowly rising prostate-specific antigen levels would prevent chemotherapy use. The decision to retreat with chemotherapy was largely driven by prior response to first-line chemotherapy, with docetaxel preferred for those responding. Many (78%) felt that UK clinical practice was likely to change over the next 5 years, and that abiraterone acetate, MDV3100 and cabazitaxel would have the most positive impact. Opinions regarding the future use of aflibercept and custirsen were mixed. Few (≤3%) would use zibotentan or bevacizumab in the future based on recent negative phase III study results, or because of cost and complexity for sipuleucel-T.. Although emerging therapies for mCRPC mean that the future is bright, guidelines are needed to ensure optimum use and sequencing of treatments. Additional costs and anticipated workload associated with new agents will require careful consideration.

Topics: Androgen Antagonists; Androstenes; Androstenols; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Attitude of Health Personnel; Benzamides; Bevacizumab; Forecasting; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Practice Patterns, Physicians'; Prostatic Neoplasms; Pyrrolidines; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retreatment; Surveys and Questionnaires; Taxoids; Therapies, Investigational; Thionucleotides; Tissue Extracts; Urology

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Drug Resistance, Neoplasm; Fatal Outcome; Humans; Male; Neoplasm Recurrence, Local; Prednisolone; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Treatment Outcome

Topics: Antineoplastic Agents; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Topics: Aged; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Evidence-Based Medicine; Humans; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Practice Guidelines as Topic; Prognosis; Prostatic Neoplasms; Remission Induction; Survival Analysis; Taxoids; Treatment Outcome; United Kingdom

The management of patients with metastatic castration-resistant prostate cancer is a real challenge. Indeed, after a first line chemotherapy with docetaxel, there was no standard because the treatments were ineffective. Today, several therapeutic options are available with the development of new therapies. Among them, cabazitaxel, semi-synthetic derivative of a natural taxoid, has been developed to its low recognition by the MDR system and power distribution including brain. This new chemotherapy was assessed in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy. Treatment with cabazitaxel plus prednisone has improved overall survival of 2.4 months compared to mitoxantrone in the TROPIC phase III. However, hematologic toxicity may be limiting with a risk of febrile neutropenia; hematopoietic growth factors are advised in case of significant neutropenia. The cabazitaxel, Jevtana(®), has been approved in second line after docetaxel. Its position in relation to new types of hormone therapy, as abiraterone acetate, in the same indication requires further investigations, including predictive factors of response. Studies are on going in first line indication (compared to docetaxel) and associated to other new hormone therapies.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Mitoxantrone; Prednisolone; Prostatic Neoplasms; Taxoids

Topics: Antineoplastic Agents; Continuity of Patient Care; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Clearly, no neoplasm other than prostate cancer has benefited from so many breakthroughs since the beginning of this decade: the past two years can be considered exceptional due to the number of emerging agents against castration-resistant prostate cancer (CRPC), which have demonstrated positive outcomes in phase III trials. Until 2010, docetaxel (Taxotere) was the only agent capable of improving survival in patients with metastatic CRPC. Since then, positive results from phase III trials have been reported for sipuleucel-T, cabazitaxel, denosumab, abiraterone, radium-223, and enzalutamide, while other promising agents including notably orteronel, ipilimumab and cabozantinib are currently under study. Taken together, the incorporation of these agents in the routine management of patients with CRPC is likely to expand their median life expectancy, which was only ∼1 year until the early 2000, to >30 months in the near future. The availability of these agents will lead to new challenges and questions, such as: Can our societies afford the costs? Should we use these agents sequentially or in combination with an incremental benefit? Can we personalise treatment based on the biology of the individual's disease? How will we develop new active compounds in the context where a half dozen approved agents may confound their potential overall survival effect?

Topics: Androgen Antagonists; Androstenes; Androstenols; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Bone Neoplasms; Clinical Trials, Phase III as Topic; Denosumab; Docetaxel; Humans; Ipilimumab; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Taxoids; Tissue Extracts; Tumor Microenvironment

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Male; Oncology Nursing; Prostatic Neoplasms; Taxoids

This article reviews the initial experience with chemotherapy in metastatic castration-resistant prostate cancer (mCRPC) and outlines some of the ongoing clinical trials in this area. In addition, the authors outline current knowledge on outcomes of patients treated with taxane-based chemotherapy on retrospective analysis of randomized trials. These data are intended to provide physicians and patients with a general idea on the outcomes of men with mCRPC that may facilitate clinical decisions as well as the design and evaluation of clinical trials.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Cytotoxins; Disease Progression; Docetaxel; Drug Therapy, Combination; Estramustine; Humans; Male; Mitoxantrone; Neoplasms, Hormone-Dependent; Prognosis; Prostatic Neoplasms; Taxoids; Treatment Outcome

The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m(2) every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids

Discoveries of molecular mechanisms and therapeutic targets in metastatic castration-resistant prostate cancer (CRPC) have led to significant advancements in the development of effective agents in this setting, with diverse mechanisms of action. Within the past 2 years, 5 agents have been approved for the treatment of patients with metastatic CRPC (cabazitaxel, abiraterone, sipuleucel-T, denosumab, and enzalutamide), and another (Alpharadin) has shown overall survival benefit in a phase III trial. This article summarizes the phase III data showing clinical benefit from these agents, highlights other promising therapies in phase III studies as single agents (PROSTVAC-VF, ipilimumab, cabozantinib), discusses important unanswered questions regarding these therapies, and provides a schema for their use based on current regulatory approval and how this is likely to evolve as data from ongoing studies are reported. Although curative interventions in metastatic CRPC still do not exist, the hope is that optimization of therapeutic strategies can reduce the morbidity and mortality associated with this disease.

Topics: Antineoplastic Agents, Hormonal; Bone Neoplasms; Clinical Trials, Phase III as Topic; Humans; Immunotherapy; Male; Molecular Targeted Therapy; Neoplasms, Hormone-Dependent; Prostatic Neoplasms; Radiopharmaceuticals; Taxoids

At the 2010 meeting of the European Society for Medical Oncology (ESMO), a landmark development in prostate cancer therapy was unveiled. In a phase III study, the CYP17 inhibitor abiraterone yielded a survival advantage over placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed despite prior docetaxel therapy. The data for abiraterone follow the publication of successful phase III studies earlier this year supporting two mechanistically distinct agents-namely, the novel taxane cabazitaxel and the autologous dendritic cell vaccine sipuleucel-T. A challenge that lies ahead for the scientific community is to discern the appropriate positioning of abiraterone in an increasingly crowded therapeutic landscape. Several ongoing trials are examining the agent in earlier settings (i.e., a phase III in mCRPC pre-docetaxel, and smaller studies in combination with radiation therapy or as neoadjuvant pre-surgery for localized disease). Herein, several potential strategies for abiraterone are presented to clarify the clinical utilization of this agent in the future.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts

Topics: Antineoplastic Agents; Docetaxel; Drug Approval; Humans; Male; Mitoxantrone; Orchiectomy; Prostatic Neoplasms; Taxoids

Treatment with docetaxel-based chemotherapy results in improved survival in patients with metastatic castration-resistant prostate cancer. However, all patients eventually develop progressive disease associated with poor outcomes. In this article, we discuss the available second-line therapeutic options following docetaxel, with a special focus on cabazitaxel, which is the first agent to yield extended survival as second-line therapy following docetaxel. Cabazitaxel, a novel semi-synthetic taxane, is effective even in docetaxel-resistant model systems. Recently, results of the Phase III TROPIC trial demonstrated improved survival with cabazitaxel plus prednisone compared with mitoxantrone and prednisone in patients with progressive metastatic castration-resistant prostate cancer, following prior docetaxel, which led to approval by the US FDA.

Topics: Adrenal Cortex Hormones; Aged; Animals; Antineoplastic Agents; Caco-2 Cells; Castration; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; HL-60 Cells; Humans; Leukemia P388; Male; Mice; Middle Aged; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Male; Mitoxantrone; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Failure; Treatment Outcome

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Male; Mitoxantrone; Prednisone; Prostatic Neoplasms; Stroke Volume; Taxoids; Treatment Failure; Treatment Outcome

The biological basis of the selective outgrowth of disseminated prostate cancer cells within the hematopoietic bone microenvironment remains a compelling biological mystery. A major proportion of the morbidity and mortality related to prostate cancer can be traced to the burden of bone metastases. The optimal management of bone health in men with prostate cancer requires control of the underlying epithelial neoplasm, attenuation of the subverted bone remodeling process that accompanies disease progression, reduction in the bone complications of disease-directed therapy, and management of co-existing comorbidities that enhance bone fragility. While bone-homing radioisotopes, bisphosphonates, and RANK ligand inhibitors have demonstrated reduction in bone pain and/or other skeletal-related events, further advances into definitive improvements in survival and/or global quality of life are required. A deeper understanding of the biology of bone metastases will likely facilitate a bone-directed therapeutic approach toward a major impact on the survival of men with this important disease.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Neoplasms; Clinical Trials as Topic; Denosumab; Diphosphonates; Humans; Male; Prostatic Neoplasms; RANK Ligand; Taxoids; Tissue Extracts

Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents (sipuleucel-T, cabazitaxel and abiraterone) with distinct mechanisms of action. Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Cancer Vaccines; Clinical Trials, Phase III as Topic; Humans; Male; Neoplasm Metastasis; Orchiectomy; Prostatic Neoplasms; Taxoids

As the number of men in the United States 65 years of age or older increases--from 12% in 2000 to 20% in 2030--the burden of prostate cancer also is increasing. Standard therapy is appropriate for healthy men with a life expectancy of more than 10 years; however, clinicians may fear either overtreating frail patients or undertreating patients who are physically fit. Evidence suggests the best approach is to conduct a comprehensive geriatric assessment using available measures and published guidelines to individualize treatment plans. Recent Food and Drug Administration approval of cabazitaxel, sipuleucel-T, and denosumab has expanded available treatment options. Managing symptoms related to disease complications and side effects of treatment is increasingly more complicated with the addition of these new regimens and extended life expectancy. Pharmacists' participation in patient assessment and supportive care are necessary components of comprehensive care for cancer patients.

Topics: Age Factors; Aged; Antibodies, Monoclonal, Humanized; Denosumab; Geriatric Assessment; Humans; Life Expectancy; Male; Patient Care; Pharmacists; Prostatic Neoplasms; Taxoids; Tissue Extracts

Although treatment for prostate cancer has improved over the past several years, taxanes remain the only form of chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In addition to the promising therapeutic cancer vaccines and newly developed agents targeting androgen receptor signaling, chemotherapy-based treatments will likely continue to play a significant role in patients with mCRPC. Recently published data that showed that a second taxane (cabazitaxel) extends survival after progression on docetaxel was a significant step forward, but also highlighted the need to overcome taxane resistance in prostate cancer. Preliminary evidence suggests that several treatment strategies may improve the activity of taxanes in prostate cancer and perhaps enhance clinical outcomes.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

Topics: American Medical Association; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Denosumab; Humans; Male; Prostatic Neoplasms; RANK Ligand; Taxoids; Terminology as Topic; Tissue Extracts; United States; United States Food and Drug Administration

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Glucocorticoids; Humans; Male; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Taxoids; Treatment Outcome

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents; Combined Modality Therapy; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prostatic Neoplasms; Radiotherapy; Taxoids

Within the past two years, three agents have garnered approval from the US FDA for the specific treatment of metastatic castration resistant prostate cancer (mCRPC) - (1) abiraterone, (2) cabazitaxel and (3) sipuleucel-T. In separate phase III studies, each agent led to an improvement in overall survival (OS) of 2-4 months over a suitable comparator. With these costly therapies all having potential application in the patient with mCRPC, multiple entities (industry, government, and the general public) must strategize to determine how the cost burden of these agents can be balanced with the potential gains for the individual patient. Herein, we provide a framework with which to approach this dilemma.

Topics: Androstenes; Androstenols; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Drug Costs; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts

Topics: Androgen Antagonists; Androstenes; Androstenols; Antineoplastic Agents; Disease Progression; Disease-Free Survival; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Steroid 17-alpha-Hydroxylase; Taxoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prednisone; Prostatic Neoplasms; Taxoids

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Approval; Drug Discovery; Humans; Male; Prednisone; Prostatic Neoplasms; Taxoids; United States; United States Food and Drug Administration

The FDA has approved 2 new treatments for castration-resistant (formerly called hormone-refractory) prostate cancer. Sipuleucel-T (Provenge - Dendreon) s the first immunotherapy approved for treatment of prostate cancer. Cabazitaxel (Jevtana - Sanofi-Aventis) is approved for second-line treatment of metastatic castration-resistant prostate cancer previously treated with docetaxel (Taxotere).

Topics: Cancer Vaccines; Drug Interactions; Humans; Immunotherapy; Male; Neoplasm Metastasis; Prostatic Neoplasms; Taxoids; Tissue Extracts

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Clinical Trials as Topic; Docetaxel; Drug Approval; Drug Resistance, Neoplasm; Estramustine; Humans; Male; Mitoxantrone; Prednisone; Prostatic Neoplasms; Quality of Life; Taxoids; Tissue Extracts

Prostate cancer is the second most frequently diagnosed cancer in men and the fifth most common cancer overall. Globally, more than 900,000 new cases of prostate cancer will be diagnosed in 2010 and more than 260,000 will, unfortunately, die from the disease. In the US, an estimated 217,000 new cases of prostate cancer and 32,000 deaths are expected this year. Definitive therapy (surgery or radiation) is highly effective, but if the tumor escapes the gland, treatment options are limited. For this population of patients, androgen suppression is the cornerstone of initial therapy. Furthermore, progression to castration resistant prostate cancer (CRPC) is inevitable. The current front-line treatment for patients with CRPC is the chemotherapeutic agent docetaxel (administered every 3 weeks). Until now, it is the only agent that has been shown to prolong survival in CRPC. The approval trial for docetaxel found a median overall survival of 19.2 months for patients receiving docetaxel plus prednisone compared to 16.3 months for patients receiving mitoxantrone plus prednisone (p=0.0094). Mitoxantrone plus prednisone is often utilized for its palliative benefits, but two randomized trials failed to demonstrate a survival advantage.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Docetaxel; Humans; Male; Prednisone; Prostatic Neoplasms; Taxoids; Tubulin

Topics: Androstenes; Androstenols; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Drug Resistance, Neoplasm; Drugs, Investigational; Humans; Male; Neoplasms, Hormone-Dependent; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Taxoids; Testosterone; Tissue Extracts

Topics: Antineoplastic Agents, Phytogenic; Humans; Male; Neoplasm Metastasis; Patient Education as Topic; Prostatic Neoplasms; Taxoids

Topics: Antineoplastic Agents; Clinical Trials as Topic; Gonadotropin-Releasing Hormone; Humans; Male; Orchiectomy; Prostatic Neoplasms; Taxoids; Tissue Extracts