cabazitaxel and Neoplasm-Metastasis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes.. The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR).. Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2-4.4) and 15.2 months (95% CI 11.3-19.4), respectively. Regarding toxicity, grade 3-4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment.. This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity.

Topics: Adult; Aged; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Metastasis; Receptor, ErbB-2; Survival Analysis; Taxoids; Treatment Outcome

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

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

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

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

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

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

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

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

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

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

This is a single-arm study (NCT01956149) to determine the prolonged (≥ 4 months) disease control rate with cabazitaxel administered in second-(or later) setting for patients with advanced or metastatic adenocarcinoma of the esophagogastric junction (EGJ) and stomach.. 65 patients with advanced EGJ and stomach cancer were treated with 20 mg/m. 65 patients (median age: 63, range 31-86 years) were assigned to treatment. Median no. of prior therapies that had received prior taxane therapy was 2. 80%. Patients received a median of two cycles of cabazitaxel. Efficacy results are for the ITT population. The mDCR in n = 65 patients was 10.8% (95% CI 4.4-20.9%). There was a control of disease (CR + PR + SD) in n = 26 patients of n = 65, corresponding to a DCR of 40.0% (95% CI 28.0-52.9%). In patients without prior taxane use, it was 46.2% (95% CI 25.1-80.8%) and in patients with only one prior therapy, DCR was 50.0% (95% CI 31.3-68.7%). The median overall survival was 4.6 months (95% CI 3.16, 5.59) in the whole ITT population. In patients with only one prior therapy, median OS was 5.4 months (95% CI 2.60, 7.43) and in patients without taxane pretreatment, it was 6.4 months (95% CI 1.38, 14.17). The median progression-free survival time was 1.5 months (95% CI 1.32, 2.27) in the whole ITT population, 2.9 months (95% CI 0.72, 4.67) without prior taxane therapy and was 1.7 (95% CI 1.28, 3.35) months in patients with only one prior therapy median.. Cabazitaxel is active in heavily pretreated patients with metastatic and advanced esophagogastric junction and gastric adenocarcinoma. Efficacy results in a classic second-line population are comparable to other second-line studies, therefore, under the limitations of this trial, (single arm, Phase II design) cabazitaxel might be an option especially in patients without prior taxane therapy, in second line and even further line therapy of metastatic and advanced esophagogastric junction and gastric adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Disease Progression; Esophageal Neoplasms; Esophagogastric Junction; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Stomach Neoplasms; Taxoids

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

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

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

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

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

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

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

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

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

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

We aimed to identify SNPs associated with cabazitaxel toxicity and response within a Phase II clinical trial using this compound in advanced transitional cell carcinoma after progression to a platinum-based regimen.. Eleven SNPs in CYP3A4, CYP3A5, CYP2C8, ABCB1 and TUBB1 were genotyped in 45 patients.. CYP3A5 rs776746 A allele was associated with protection against gastrointestinal toxicity (odds ratio: 0.06, 95% CI: 0.007-0.63, p = 0.018) and with reduced progression-free survival (hazard ratio: 5.1, 95% CI: 1.7-15.1, p = 0.0038, multivariable analysis). ABCB1 SNPs were associated with total number of grade 3-4 toxicity events (p-values of 0.009, 0.041 and 0.043, respectively).. Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Carcinoma, Transitional Cell; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Polymorphism, Single Nucleotide; Taxoids; Tubulin; Urinary Bladder Neoplasms; Urothelium

Taxane-gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15-20 mg/m) before (part 1a) or after (part 1b) gemcitabine (700-1000 mg/m) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m cabazitaxel plus 1000 mg/m gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3-4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Taxoids

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

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

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

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

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

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

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

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

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

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

Most patients with metastatic breast cancer (MBC) progress after chemotherapy. Cabazitaxel (XRP6258) is a new taxoid that is active in chemotherapy-resistant tumour cell lines. The objectives of this phase I/II study were to assess the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with MBC who had been previously treated with taxanes and anthracyclines.. In part I, we used a 3+3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice daily (days 1-14) every 3 weeks. In part II, we evaluated the objective response rate (ORR) at the MTD.. Thirty-three patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20mg/m(2) plus capecitabine 1000 mg/m(2) was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3-4 toxicities were asthenia (n=5), hand-foot syndrome (n=5), neutropenia (n=21), neutropenic infection (n=1), and neutropenic colitis (n=1). One patient had febrile neutropenia. Antitumour activity was observed at all dose-levels with two complete responses, five partial responses (PRs), and 20 disease stabilisations (seven unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8% (95% CI: 8.2-47.2%). The median response duration was 3.1 months (95% CI: 2.1-8.4 months), with four of five lasting for more than 3 months. Median time to progression was 4.9 months.. Cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

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

To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity.. Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course.. Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses.. The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Neutropenia; Taxoids

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

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

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

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

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

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

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

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

Outcomes of multiply relapsed, refractory germ-cell tumour (GCT) patients remain poor with an overall survival (OS) of a few months only. Thus, new therapeutic advances are urgently needed. Cabazitaxel has shown preclinical activity in platinum-resistant GCT models. Here, we report the first clinical case series of cabazitaxel treatment for platinum-refractory GCT.. Data of multiply relapsed GCT patients receiving single-agent cabazitaxel were retrospectively analysed. Endpoints included 12-week progression-free survival (PFS) rate, disease control rate, tumour marker responses, median PFS and OS, and toxicity.. Cabazitaxel showed limited activity in 13 heavily pre-treated GCT patients. After a median follow-up of 23 weeks (IQR 29), 69% of patients were deceased. A median of 2 cycles of cabazitaxel (range 1-7) were applied. The 12-week PFS rate was 31%. Median PFS and OS were 7 and 23 weeks, respectively. Two patients achieved objective responses (15%), three patients (23%) achieved a tumour marker decline ≥ 50%, and the disease control rate was 39%. Cabazitaxel was well tolerated. CTCAE° III-IV haemato-toxicity was most common (54%), and dose reductions were scarce (15%).. In this case series, cabazitaxel showed limited activity in heavily pre-treated GCT patients. Two-phase II studies are underway (NCT02115165, NCT02478502) prospectively assessing cabazitaxel in multiply relapsed GCTs.

Topics: Adult; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; Humans; Male; Mediastinal Neoplasms; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal; Retroperitoneal Neoplasms; Retrospective Studies; Taxoids; Testicular Neoplasms

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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, Phytogenic; Humans; Male; Neoplasm Metastasis; Patient Education as Topic; Prostatic Neoplasms; Taxoids