Docetaxel in the management of prostate cancer: current standard of care and future directions

Background: Advanced and metastatic prostate cancer continues to represent a significant healthcare burden. Since the publication of two randomized trials that showed significant survival and palliative benefits for men treated with docetaxel, this drug has become the treatment of choice for patients with metastatic castration resistant prostate cancer (CRPC). Objective: This review discusses the development and current use of docetaxel in metastatic CRPC, as well as future clinical applications. Methods: The current literature, meeting abstracts and ClinicalTrials.gov have been reviewed. The most relevant studies involving patients with prostate cancer receiving therapy with docetaxel, alone or in combination with other agents, have been summarised. Conclusion: Docetaxel monotherapy is the approved treatment for patients with metastatic CRPC, and its association with other agents, such as targeted therapies, is currently under study. Several trials are currently ongoing to investigate the use of docetaxel in the early stages of disease, particularly in the neoadjuvant and adjuvant settings for patients with high-risk disease.     

MDV3100 for the treatment of prostate cancer

INTRODUCTION: MDV3100 is a rationally designed androgen receptor antagonist, which has recently been shown to improve survival in men with metastatic castration-resistant prostate cancer previously treated with docetaxel chemotherapy. Drug development for advanced prostate cancer is advancing at a rapid pace with four other novel therapies (abiraterone, cabazitaxel, alpharadin and sipuleucel-T) also shown to improve overall survival in large randomised studies. AREAS COVERED: This review will cover the historical background of androgen deprivation therapy, recently approved agents for advanced prostate cancer, an overview of the clinical development of MDV3100 and an analysis of how MDV3100 may fit into future treatment protocols for this disease. EXPERT OPINION: Full analysis of safety and efficacy data is awaited; however, MDV3100 appears to be a well-tolerated addition to the expanding portfolio of effective drugs for the treatment of advanced prostate cancer.     

Cabazitaxel, a new taxane with favorable properties

Cabazitaxel is a new taxane characterized by convenient administration, a favorable pharmacokinetic and safety profile and a decreased propensity for P-glycoprotein (Pgp)-mediated drug resistance. In preclinical studies cabazitaxel inhibited cell growth in a wide range of human cancer cell lines, including tumor models expressing Pgp. Phase I clinical trials established that the cabazitaxel side effect profile is similar to that reported for taxanes, with neutropenia and neuropathy being the most commonly reported toxicities. Further clinical studies have revealed that cabazitaxel is clinically active in women with taxaneresistant metastatic breast cancer and in men with metastatic castration-resistant prostate cancer previously treated with docetaxel. The TROPIC phase III trial concluded that, compared to mitoxantrone/prednisone, the combination cabazitaxel/prednisone conferred a statistically significantly longer overall survival in patients after treatment with a docetaxel-containing regimen, providing the basis for its FDA approval in 2010.     

恩扎卢胺治疗前列腺癌的快速卫生技术评估

目的：快速评估恩扎卢胺（ENZ）治疗前列腺癌的有效性、安全性和经济性,为临床合理用药和决策者提供参考。方法：计算机检索PubMed、Web of Science、Cochrane Library、Scopus、Embase、EBSCO、CNKI、Wanfang Data、VIP、CBM数据库和国内外卫生技术评估（HTA）相关网站,纳入ENZ相关的HTA报告、系统综述/Meta分析和经济学评价。由2位研究员依据纳入排除标准筛选文献、数据提取和质量评价,并对结果进行定性分析。结果：共纳入51篇文献,包含4篇HTA报告,36篇系统综述/Meta分析和11篇经济学评价。有效性和安全性方面,对于非转移性去势抵抗性前列腺癌（nmCRPC）,与安慰剂或达罗他胺相比,ENZ可显著延长无进展生存期（PFS）和无转移生存期（MFS）;与安慰剂相比,显著增加不良事件的发生风险。对于转移性去势抵抗性前列腺癌（mCRPC）,与安慰剂、阿比特龙、卡巴他赛和Sipuleucel-T相比,ENZ可显著延长PFS;与安慰剂相比,显著增加高血压和疲劳的发生风险。对于转移性激素敏感性前列腺癌（mHSPC）,与雄激素剥夺治疗（ADT）、多西他赛联合ADT相比,ENZ联合ADT可显著延长PFS和OS。经济性方面,与阿比特龙相比,ENZ治疗化疗初治或内脏mCRPC患者具有成本-效果优势。结论：ENZ治疗前列腺癌具有良好的有效性和安全性,经济性有待进一步研究。     

Role of second-line systemic treatment post-docetaxel in metastatic castrate resistant prostate cancer- current strategies and future directions

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.     

Hormone refractory prostate cancer (HRPC): present and future approaches of therapy

The mainstay of therapy for patients with advanced prostate cancer still remains androgen deprivation, although response to this is invariably temporary. Most of the patients develop hormone-refractory disease resulting in progressive clinical deterioration and, ultimately, death. Until recently there has been no standard chemotherapeutic approach for hormone refractory prostate cancer (HRPC), the major benefits of chemotherapy being only palliative. The studies combining mitoxantrone plus a corticosteroid demonstrated that chemotherapy could be given to men with symptomatic HRPC with minimal toxicity and a significant palliation could be provided. Recently, results from 2 phase III randomized clinical trials demonstrating that a combination of docetaxel plus prednisone can improve survival in men with HRPC have propelled docetaxel-based therapy into the forefront of treatment options for these patients as the new standard of care. There is a promising activity of new drug combinations such as taxanes plus vinca alkaloids; bisphosphonates are assuming a prominent role in prostate therapy through their ability to prevent skeletal morbidity. Combinations of classic chemotherapeutic agents and biological drugs began to be tested in phase II-III trials and the first results appear interesting. This article focuses on combinations recently evaluated or under clinical development for the treatment of HRPC.     

Radium-223 Chloride: A New Treatment Option for Metastatic Castration-Resistant Prostate Carcinoma

In the last few years, the treatment of castration-resistant prostate carcinoma (CRPC) has changed completely. The approval of docetaxel and subsequent investigation in this field have led to development of new agents that have demonstrated an improvement in overall survival in the post-docetaxel setting, such as cabazitaxel and abiraterone. Radium-223 chloride is a radioisotope that has recently shown efficacy after docetaxel and in patients unfit for docetaxel, with improvements in overall survival and the time to the first skeletal-related event, compared with placebo, without increasing toxicity. These findings have made this agent a new option for treatment of these patients in the near future.     

Zibotentan for the treatment of castrate-resistant prostate cancer

Importance of the field: Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.

Areas covered in this review: This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ET_A receptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ET_A receptor.

What the reader will gain: Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.

Take home message: Modulating the activity of ET-1 through the ET_A receptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ET_A inhibitor, to determine the effect of this agent on overall survival in these patients.     

Management of metastatic castration-resistant prostate cancer: recent advances

Metastatic prostate cancer remains a considerable therapeutic challenge; however, advances in clinical research have resulted in five new treatments in the last 2 years. The immunotherapy sipuleucel-T, the cytotoxic cabazitaxel, the androgen biosynthesis inhibitor abiraterone acetate, the radioisotope alpharadin and the anti-androgen MDV3100 have all been shown to improve overall survival in randomized phase III studies for patients with metastatic castration-resistant prostate cancer. The therapeutic strategies of targeting androgen-receptor signalling and other key intracellular pathways involved in tumour progression and treatment resistance are yielding promising results. Agents such as the dual vascular endothelial growth factor receptor/MET inhibitor cabozantinib, the clusterin inhibitor custirsen and the Src inhibitor dasatinib have shown encouraging results in phase II studies. Novel immunotherapeutics such as prostate-specific membrane antigen-directed therapy and the anti-cytotoxic T lymphocyte-associated receptor 4 (CTLA4) antibody ipilimumab are also under investigation. Optimal methods of treatment selection, combination and sequencing have yet to be determined.     

Doxetaxel: new indication. Prostate cancer: a few more weeks

(1) The standard treatment for metastatic prostate cancer is hormone therapy, based on medical castration (with an LH-RH agonist) or surgical castration (pulpectomy), possibly combined with an androgen antagonist. For patients with hormone-resistant disease the only cytotoxic agents approved in France, estramustine and mitoxantrone, have no proven impact on survival. (2) Docetaxel is now approved in Europe for the treatment of hormone-resistant metastatic prostate cancer, in combination with a steroid. (3) In an open-label comparative trial involving 1006 patients, docetaxel infusion at a dose of 75 mg/m2 every 3 weeks, in combination with prednisone (or prednisolone), significantly extended the median survival time by about 2.5 months as compared with a mitoxantrone-prednisone combination (18.9 versus 16.5 months). In another open-label comparative trial involving 674 patients, a combination of docetaxel + estramustine was significantly more effective than a mitoxantrone + prednisone combination in extending median survival time (17.5 versus 15.6 months). (4) The adverse effects of docetaxel + prednisone were the same as those seen with other indications (hair loss, nausea and vomiting, diarrhea, neutropenia, nail disorders, neuropathies), and were severe in 25% of patients. (5) In France the cost of docetaxel therapy for hormone-resistant metastatic prostate cancer is more than 1000 euros every three weeks. (6) In practice, docetaxel is the first cytotoxic agent shown to prolong survival in men with hormone-resistant metastatic prostate cancer. The benefit is limited, however, especially given the potentially severe adverse effects of docetaxel, which must be disclosed to patients.     

Advancing therapies in metastatic castration-resistant prostate cancer

ABSTRACT

Introduction: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T.

Areas covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies.

Expert opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival.     

Systemic nonhormonal management of advanced prostate cancer and its likely impact on patients' survival and quality of life

Prostate cancer is a hormonal sensitive disease with a response rate ranging from 80 to 90%; however, the majority of patients develop hormone resistance resulting in poor long term survival. Chemotherapy has demonstrated a benefit over steroids in improving the quality of life in the hormone refractory phase. Furthermore, the introduction of docetaxel succeeded in improving the survival of these patients in first-line therapy. Second-line treatment following docetaxel is challenging with no agent classified as standard in this setting. In the last 5 years, several drugs have shown promising results in initial evaluation. However, randomized phase III trials would be needed to answer this question. The majority of patients develop bone metastasis and the use of bisphosphonates has yielded encouraging results. Our understanding of the biology of hormone refractory prostate cancer has improved dramatically over the past few years and has translated into the developments of new therapeutic targets for this disease. Agents affecting several targets, including calcitriol, endotheline-1, bcl-2, and angiogenesis, are being studied currently and have the potential to change the treatment paradigms of this otherwise fatal disease. This review focuses on current and potential treatment options, including cytotoxic agents, bisphosphonates, and targeted agents, for patients with hormone refractory prostate cancer and the impact of these options on survival and quality of life.     

New therapeutic strategies for castration-resistant prostate cancer

Docetaxel has until recently been the only agent with a small survival benefit for metastatic castration-resistant prostate cancer (CRPC). To improve clinical outcome in CRPC, numerous classes of drugs targeting specific pathways involved in hormone action, bone metabolism, angiogenesis, apoptosis and immune response have currently been investigated concerning the efficacies of either single agents or combinations with docetaxel. Noteworthy, current two phase III trials of cabazitaxel and sipuleucel-T have demonstrated significant improvements of overall survival in CRPC. From the viewpoint of complexity of mechanisms implicated in prostate cancer progression, effective therapeutic strategies should be developed by multifaceted approaches, such as the composition of novel agents targeting for key molecules, cytotoxic chemotherapy, and immunotherapy. The recent patented molecules (e.g., hyaluronidase, caveolin, Bag1-L, N-cadherin, AR splicing variants, PCGEM-1) have a strong potential as therapeutic options for CRPC. Here, we review the newest evidence of novel agents and patented compounds and methods for the purpose of the future use in CRPC.     

Docetaxel: a review of its use for the first-line treatment of advanced castration-resistant prostate cancer

Docetaxel (Taxotere?) is a well established anti-mitotic chemotherapy agent. Among other therapeutic indications, docetaxel plus prednisone is indicated for first-line chemotherapy in patients with castration-resistant prostate cancer (CRPC). Docetaxel every 3 weeks plus continuous prednisone has been standard first-line chemotherapy in CRPC since demonstrating improved survival compared with the previous standard regimen, mitoxantrone plus prednisone, in the phase III TAX 327 trial in 2004. Since that time, docetaxel has been combined with various agents that demonstrated additive or synergistic activity in preclinical studies in an effort to further improve outcomes, but to date, overall survival has not been extended compared with docetaxel plus prednisone. However, several promising agents are emerging with a potential role in docetaxel-based combinations based on efficacy and manageable toxicity, including bevacizumab, dasatinib and atrasentan. In the TAX 327 trial, neutropenia was relatively common in the group receiving 3-weekly docetaxel plus prednisone, but infection was rare. The tolerability of a weekly docetaxel regimen also administered in this trial was not significantly different to that of the 3-weekly regimen, except for a lower incidence of grade 3 or 4 neutropenia. However, weekly or 2-weekly docetaxel administration schedules may have a place in very elderly or frail patients in order to improve tolerability compared with the 3-weekly regimen. In conclusion, docetaxel every 3 weeks plus prednisone remains the optimum first-line chemotherapy for most patients with advanced CRPC until such time that ongoing research with docetaxel and emerging therapeutic agents can demonstrate improved survival.     

Which drug combination for hormone-refractory prostate cancer?

Patients with metastatic hormone-refractory prostate cancer have a progressive disease with a median survival of approximately 11 months, and currently no treatment offers a survival advantage. The standard drug treatment is a corticosteroid and chemotherapy with mitoxantrone. In a comparison of docetaxel every 3 weeks and prednisone, versus mitoxantrone and prednisone, with a follow-up of approximately 21 months, there were less deaths in the docetaxel group than in the mitoxantrone group (166 of 335 patients and 201 of 337 patients, respectively). Docetaxel also prolonged the duration of survival compared with mitoxantrone (18.9 and 16.5 months, respectively). When given with prednisone, docetaxel was also shown to reduce pain and serum prostate specific antigen levels and improve quality of life compared with mitoxantrone/prednisone. In another trial in hormone-resistant prostate cancer patients, which compared docetaxel and estramustine with mitoxantrone and prednisone during a median follow-up of 32 months, there were fewer deaths with docetaxel/estramustine than with mitoxantrone/prednisone, which were 217 of 338 and 235 of 336 patients, respectively. Median survival was also longer in the docetaxel and estramustine group than in the mitoxantrone/prednisone group (17.5 and 15.6 months, respectively). In conclusion, two combinations (docetaxel/prednisone and docetaxel/estramustine) have been shown to be superior to mitoxantrone/prednisone in hormone-refractory prostate cancer and both should be considered for use. With the present information, there is little to distinguish between these combinations.     

Abiraterone acetate: redefining hormone treatment for advanced prostate cancer

Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling. Abiraterone acetate (AA) is a rationally designed CYP17 inhibitor that blocks the conversion of androgens from non-gonadal precursors effectively, thus reducing testosterone to undetectable levels. AA has recently been proved to extend survival for men with metastatic castration-resistant prostate cancer who have progressive disease after first-line chemotherapy treatment. In addition, it is currently being tested in a Phase III trial in the pre-chemotherapy setting. This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research.     

Trastuzumab: new indication. Metastatic breast cancer, in combination with docetaxel: promising, but more evaluation is needed

(1) There is no consensus on the optimal chemotherapy for metastatic breast cancer. Patients who have never previously received chemotherapy are generally given an anthracycline-based combination of cytotoxic agents. Options for patients who have already received an anthracycline include a taxane such as paclitaxel or docetaxel. The median survival time with these treatments is only about 2 to 2.5 years. (2) Trastuzumab is a monoclonal antibody directed against HER-2, a protein overexpressed by certain tumours, including about 25% of breast tumours. In 2000, the approved indications included first-line treatment of metastatic breast cancer in combination with paclitaxel. One clinical trial had shown, albeit with a low level of evidence, a median increase in survival of about 4 to 5 months. Trastuzumab is now approved for first-line treatment of metastatic breast cancer, in combination with docetaxel. (3) Evaluation data include the results of an open-label trial comparing docetaxel + trastuzumab with docetaxel monotherapy in 186 patients. The median survival time was significantly longer with the combination (31.2 versus 22.7 months). There are no relevant comparisons with other widely used cytotoxic drugs. Indirect comparison suggests that survival is similar with docetaxel + trastuzumab and paclitaxel + trastuzumab. (4) Data on the trastuzumab-docetaxel combination confirm the known adverse effects of trastuzumab, which include heart failure and diarrhea. Trastuzumab increases the frequency of docetaxel-induced neutropenia, which carries a risk of infections. (5) In summary, the results of clinical trials show that median survival time is increased by a few months when trastuzumab is added to a cytotoxic drug. However, the best cytotoxic agent is not known, and adverse effects are poorly documented. (6) In practice, trastuzumab has only been shown to benefit a minority of women with breast cancer, namely those whose tumours overexpress HER-2. Trastuzumab therapy is an option for metastatic breast cancer treatment, provided patients are enrolled in studies designed to answer the many outstanding questions.     

Docetaxel: new preparation. No first-line use in metastatic breast cancer

(1) For the treatment of metastatic breast cancer, the reference first-line cytotoxic chemotherapy is an anthracycline-based combination such as doxorubicin + cyclophosphamide. (2) The clinical file on docetaxel in this indication mainly comprises data from a comparative trial of doxorubicin + docetaxel versus doxorubicin + cyclophosphamide in 429 patients. (3) In this trial the doxorubicin + docetaxel combination failed to increase the duration or quality of survival relative to the doxorubicin + cyclophosphamide combination, whereas its adverse effect profile was somewhat poorer (notably with a risk of severe neutropenia). (4) Docetaxel currently has no place in this setting.     

Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin for the treatment of cancer

Background: Clusterin is a stress-induced cytoprotective chaperone protein, regulated by HSF1, and functions similarly to a small heat-shock protein. Clusterin is expressed in a variety of cancers and associated with broad-spectrum treatment resistance. Custirsen (OGX-011) is a 2′-methoxyethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA; it is currently in clinical trials for patients with cancer. Objective/methods: To review the literature on the role of clusterin in cancer progression and treatment resistance, and to summarize completed and ongoing clinical trials with custirsen. Results/conclusions: Custirsen is well tolerated in humans and biologically active in inhibiting expression of clusterin in patients with cancer. Randomized trials of custirsen in combination with chemotherapy are planned in patients with castration-resistant prostate cancer.     

Docetaxel: new indication. First-line treatment of non small-cell lung cancer: no advance

(1) The reference first-line drug therapy for patients with non-operable non small-cell lung cancer is a combination of two cytotoxic agents, one of which is a platinum compound. The survival benefit is no more than a few months. (2) The docetaxel + cisplatin combination has now been authorised in France for first-line treatment of locally advanced and metastatic non small-cell lung cancer. Evaluation data includes the results of three comparative trials. (3) In one trial the docetaxel + cisplatin combination was no more effective than the docetaxel + carboplatin combination or the vinorelbine + cisplatin combination on either the survival time (9.4 to 11.3 months) or on other endpoints. (4) Similar results were obtained in a trial versus paclitaxel + cisplatin and gemcitabine + cisplatin (median survival time 8 months in each group). (5) In a trial versus vindesine + cisplatin, the median survival time was longer with docetaxel + cisplatin (11.3 versus 9.6 months). (6) It is difficult to analyse adverse effects in these unblinded trials. Globally, the docetaxel + cisplatin combination did not appear to be safer than the comparator combinations, particularly with regard to serious events. (7) Docetaxel, like paclitaxel, is infused intravenously every three weeks. The comparator combinations tested in the three clinical trials are infused once a week. (8) In practice, for first-line treatment of inoperable non small-cell lung cancer, the docetaxel + cisplatin combination is simply one of several options, and offers no advantages in terms of survival or adverse effects.