Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

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

New developments in the treatment of castration resistant prostate cancer

In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer （CRPC） have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.     

Radium-223 in metastatic castration resistant prostate cancer

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer （mCRPC）. For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleuceI-T, cabazitaxel, abiraterone, enzalutamide and （most recently） radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer （e.g. samarium-153 and strontium-89）, radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.     

The efficacy of abiraterone acetate in treating Taiwanese chemo-refractory metastatic castration-resistant prostate cancer patients

ObjectiveTo evaluate the efficacy of abiraterone acetate in combination with prednisolone in Taiwanese men with metastatic castrate-resistant prostate cancer (mCRPC) who failed docetaxel-based chemotherapy.Materials and methodsIn this single-arm, open label study, 30 mCRPC patients with prostate specific antigen (PSA) progression after docetaxel chemotherapy were enrolled. All patients were treated with abiraterone acetate 1000 mg once daily and prednisolone 5 mg twice daily. The primary end-point was PSA response rate (defined as proportion of patients achieving a PSA decline of ≥50%). Secondary end-points were overall survival and time-to-PSA progression.ResultsAmong 28 patients who received one or more cycles of treatment, 15 (53.6%) men achieved PSA response [95% confidence interval (CI) 33.9–72.5]. The median time-to-PSA progression was 5.5 months (95% CI 3.1–7.9). The median interval from stopping abiraterone to death was 3.4 months (95% CI 0.1–21.0), and the median overall survival was 19.2 months (95% CI 13.0–25.4). The PSA responders had better overall survival compared with PSA nonresponders, in both univariate (log rank test, p = 0.007) and multivariate (Cox regression, p = 0.001; relative risk: 0.31; 95% CI: 0.12–0.76) analysis. Both a high Gleason score (≥8) and viscera involvement did not have an unfavorable response to abiraterone treatment.ConclusionA combination of abiraterone acetate and prednisolone can improve the overall survival in Taiwanese mCRPC patients who fail prior docetaxel chemotherapy.     

去势抵抗性前列腺癌患者疲乏、疼痛及生活质量的纵向分析

目的调查转移性去势抵抗性前列腺癌患者的疲乏、疼痛和生活质量情况,并分析生活质量的影响因素。方法采用简明疲乏量表、简明疼痛量表及生活质量测定量表,分别于入组时,入组后2个月、4个月和6个月对127例转移性去势抵抗性前列腺癌患者进行调查。结果入组时,入组后2个月、4个月和6个月患者疲乏得分分别为2.20、2.46、2.20和2.80,疼痛得分为1.66、1.87、1.95和2.10,生活质量得分为90.58、90.23、89.22和88.88,不同时间比较差异有统计学意义(均P0.01)。治疗方式、体力状态评分、疲乏、疼痛和年龄为生活质量的影响因素(均P0.01)。结论随着病程的进行,转移性去势抵抗性前列腺癌患者疲乏和疼痛程度逐步加重,生活质量逐步下降。护理人员应早期关注及识别患者生活质量的受损情况,早期护理介入。     

Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer

Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease. Further understanding of the biology of CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy. The treatment landscape is rapidly changing and further biologically rationale, biomarker-based ongoing clinical trials are needed. We review the recent results of major clinical trials in CRPC. New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis, microtubules, chaperones, AR and intracellular kinases, as well as immunotherapy, radiopharmaceuticals and bone-targeted agents. The recent improvement in prognosis for CRPC brings continued optimism for further improvements. Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.     

Chemotherapy and its evolving role in the management of advanced prostate cancer

Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer （CRPC）. Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing ＇level-1 evidence＇ that docetaxel-based chemotherapy led to prolongation in overall survival （OS）. This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents （e.g. abiraterone and enzalutamide） have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include： how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.