Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting

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.     

Clinical outcomes in a contemporary series of “young” patients with castration-resistant prostate cancer who were 60 years and younger

BackgroundThe prognosis of younger patients with prostate cancer is unclear, and the very few studies assessing those with metastatic castration-resistant prostate cancer (mCRPC) have mainly involved patients treated with older therapies. The aim of this observational study was to evaluate the clinical outcomes of a contemporary series of docetaxel-treated patients with mCRPC who were 60 years and younger.Patients and methodsWe retrospectively identified 134 patients who were 60 years and younger who were treated with docetaxel in 25 Italian hospitals and recorded their predocetaxel history of prostate cancer, their characteristics at the start of chemotherapy, and their postdocetaxel treatment history and outcomes.ResultsMost of the 134 consecutive patients with mCRPC received the standard 3-week docetaxel schedule; median progression-free survival (PFS) was 7 months, and 90 patients underwent further therapies after progression. The median overall survival (OS) from the start of docetaxel treatment was 21 months, but OS was significantly prolonged by the postprogression treatments, particularly those based on the new agents such as cabazitaxel, abiraterone acetate, or enzalutamide. OS was significantly shorter in the patients with a shorter interval between the diagnosis of prostate cancer and the start of docetaxel treatment; those who received hormonal treatment for a shorter period; those with shorter prostate-specific antigen doubling times; and those with lower hemoglobin levels, a worse performance status, and higher lactate dehydrogenase levels before starting treatment with docetaxel.ConclusionsThe findings of this first study of clinical outcomes in a contemporary series of younger patients with mCRPC showed that their survival is similar to that expected in unselected patients with mCRPC who were of any age.     

卡巴他赛化疗在转移性去势抵抗性前列腺癌患者中诱发前列腺特异性抗原闪烁的临床研究

目的:评估卡巴他赛治疗转移性去势抵抗性前列腺癌(mCRPC)患者中前列腺特异性抗原(PSA)闪烁的发生率和特征及其对生存时间的影响。方法:对2007年1月至2012年5月期间进行卡巴他赛二线化疗治疗的125例mCRPC患者的临床资料进行回顾性研究。收集卡巴他赛治疗前和治疗期间患者的基线特征、疾病史和PSA水平。患者的总...     

Recent advances in the therapy of castration-resistant prostate cancer: the price of progress

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

Phase III data for abiraterone in an evolving landscape for castration-resistant prostate cancer

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

New therapies for castration-resistant prostate cancer: efficacy and safety

Context

Prostate cancer (PCa) is the most common noncutaneous malignancy and the second leading cause of cancer mortality amongst men in the Western world. Up to 40% of men diagnosed with PCa will eventually develop metastatic disease, and although most respond to initial medical or surgical castration, progression to castration resistance is universal. The average survival for patients with castration-resistant prostate cancer (CRPC) is 2-3 yr.

Objective

To discuss the biologic rationale and evidence supporting current management of patients with CRPC and to review promising novel agents.

Evidence acquisition

Electronic databases (PubMed, ClinicalTrials.gov), relevant journals, and conference proceedings were searched manually for preclinical studies, clinical trials, and biomarker analyses focused on the treatment of CRPC. Keywords included castrate resistant prostate cancer and: targeted therapy, novel therapy, immunotherapy, androgen therapy, bone therapy, mechanisms, biomarkers, and trial endpoints; no time range was specified. Information pertaining to current studies was discussed with key opinion leaders.

Evidence synthesis

We focus on the efficacy and safety of approved agents, promising therapies that have proceeded to phase 3 evaluation, and those that have enhanced our understanding of the biology of CRPC. Biomarkers are considered in the context of novel targeted agents and immunotherapy.

Conclusions

CRPC has many targets. Four new agents with different mechanisms of action have recently been shown to have positive results in large phase 3 randomized trials, and have already been approved in the United States for CRPC: cabazitaxel, sipuleucel-T, denosumab, and abiraterone acetate. With our improved understanding of tumor biology and the incorporation of new prognostic and molecular biomarkers into clinical trials, we are making progress in the management of patients with CRPC.     

Serum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer

Purpose

Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC.

Optimal management of metastatic castration-resistant prostate cancer: Highlights from a European Expert Consensus Panel

The exponential growth of novel therapies for the treatment of metastatic castration-resistant prostate cancer (mCRPC) over the last decade has created an acute need for education and guidance of clinicians regarding optimal strategies for patient management. A multidisciplinary panel of 21 European experts in mCRPC assembled for comprehensive discussion and consensus development, seeking to move the field forward and provide guidance and perspectives on optimal selection and sequencing of therapeutic agents and monitoring of response to treatment and disease progression. A total of 110 clinically-relevant questions were addressed and a modified Delphi method was utilised to obtain a consensus. The panel reached a consensus on several important issues, providing recommendations on appropriate phase III clinical trial end-points and optimal strategies for imaging and monitoring of bone metastases. Guidance regarding selection and sequencing of therapy in patients with newly diagnosed or progressive mCRPC is emphasised, including the use of novel bone-targeted agents, chemotherapy, androgen receptor pathway-targeted agents and immunotherapy. The impact of drug resistance and prostate-specific antigen flare on treatment decisions was also addressed. Ultimately, individualised therapy for patients with mCRPC is dependent on continued refinement of clinical decision-making based on patient and disease characteristics. This consensus statement offers clinicians expert guidance on the implementation of recent advances to improve patient outcome, focusing on the future of prostate cancer care.     

Phase 2 Study of Cyclophosphamide,Etoposide, and Estramustine in Patients With Castration-Resistant Prostate Cancer

Background

There are no effective chemotherapies for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease has failed to respond to taxanes or patients who do not wish to receive intravenous drugs. We hypothesized that low doses of multiple medications with prolonged exposure would result in a high response rate and low toxicity.