abiraterone-acetate and cabazitaxel

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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