Expression of AR-V7 in Circulating Tumour Cells Does Not Preclude Response to Next Generation Androgen Deprivation Therapy in Patients with Castration Resistant Prostate Cancer

The androgen receptor splice variant AR-V7 has recently been discussed as a predictive biomarker for nonresponse to next-generation androgen deprivation therapy (ADT) in patients with castration-resistant prostate cancer. However, we recently identified one patient showing a response from abiraterone despite expression of AR-V7 in his circulating tumour cells (CTC).Therefore, we precisely assessed the response in a cohort of 21 AR-V7 positive castration-resistant prostate cancer patients who had received therapy with abiraterone or enzalutamide. We detected a subgroup of six AR-V7 positive patients showing benefit from either abiraterone or enzalutamide. Their progression free survival was 26 d (censored) to 188 d. Four patients displayed a prostate-specific antigen decrease of >50%. When analysing prior therapies, we noticed that only one of the six patients had received next-generation ADT prior to CTC collection.As a result, we conclude that AR-V7 status in CTC cannot entirely predict nonresponse to next generation ADT and AR-V7-positive patients should not be systematically denied abiraterone or enzalutamide treatment, especially as effective alternative treatment options are still limited.

Plasma Androgen Receptor and Docetaxel for Metastatic Castration-resistant Prostate Cancer

Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08–2.39, p = 0.018), but not PFS (HR = 1.04, 95% CI 0.74–1.46, p = 0.8) or PSA response (odds ratio = 1.14, 95% CI = 0.65–1.99, p = 0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR = 0.16, 95% CI = 0.06–0.46, p < 0.001) and PFS (HR = 0.31, 95% CI = 0.12–0.80, p = 0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR = 1.93, 95% CI = 1.19–3.12, p = 0.008) and a suggestion favoring docetaxel for AR-gained patients (HR = 0.53, 95% CI = 0.24–1.16, p = 0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial.

Activity of Cabazitaxel in Castration-resistant Prostate Cancer Progressing After Docetaxel and Next-generation Endocrine Agents

Background

Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians.

Objective

To describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents.

Design, setting, and participants

We report on a cohort of 59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of whom had received prior enzalutamide.

Outcome measurements and statistical analysis

Changes in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy.

Results and limitations

The post–endocrine-therapy patients received abiraterone (n = 32), sequential abiraterone and enzalutamide (n = 5) or enzalutamide (n = 4). These patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median of six cabazitaxel cycles (range: 1–10 cycles) were delivered, with ≥50% PSA declines in 16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naïve cohort (n = 18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis.

Conclusions

This is the first report of cabazitaxel activity in CRPC progressing after treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant cabazitaxel activity in this setting.

Patient summary

We looked at the antitumour activity of the chemotherapy drug cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after these novel endocrine treatments.     

Androgen receptor targeted therapies in metastatic castration-resistant prostate cancer – The urologists' perspective

Androgen deprivation therapy (ADT), which involves the maximal suppression of circulating testosterone, underpins the treatment approach to metastatic hormone sensitive prostate cancer. Although initial responses are generally favourable, approximately half of cases progress to metastatic castrate resistant prostate cancer (mCRPC), rendering traditional hormonal therapies ineffective. mCRPC is defined by disease progression despite established ADT. New research has improved our understanding of the the molecular mechanisms behind metastatic castration-resistant prostate cancer (mCRPC). This has led to a renewed interest in the androgen receptor as a target for therapy, paving the way for the introduction of novel androgen therapies such as abiraterone acetate and enzalutamide. Recent trials on these treatments have demonstrated their benefit to improving overall survival in the setting of mCRPC. The resultant effect is a new, constantly changing, and complex treatment paradigm for treating clinicians, who are now required to know the mechanism of actions of new medications, side effect profiles, modes of administration, and preferred sequencing of various treatment options. Furthermore, treatments involving new androgen biosynthesis are currently being developed and tested. Therefore, in the context of a highly heterogenous disease with a continuously changing treatment landscape, management of mCRPC can be particularly challenging.The purpose of this review is to provide an overview of the literature on new androgen receptor targeted therapies, and discuss the changing treatment landscape specific to metastatic CRPC.     

雄激素受体在前列腺癌中的抗凋亡效应研究进展

前列腺癌(PCa)是中老年男性多发癌症之一,目前针对晚期转移性患者的主要治疗手段是去雄激素治疗,但是绝大部分患者最终都进展为侵袭性更强的激素非依赖型PCa,而对此类患者尚无有效治疗方法。雄激素受体(AR)是前列腺上皮细胞分化与增生的基本调节因子,在调控PCa细胞存活机制方面具有非常重要作用。目前的研究结果已经表明在激素非依赖型PCa进展过程中,AR的非正常激活是关键性因素。现简要综述AR调控的PCa细胞存活机制以及针对它而设计的RNA干扰技术对PCa的治疗运用方面的进展。     

前列腺癌雄激素依赖转化后细胞内雄激素受体表达变化的研究

目的：探讨雄激素受体（AR）在前列腺癌雄激素依赖特性转化过程中的作用。方法：对33例晚期前列腺癌患者进行雄激素阻断治疗并作长时间随访,其间有18例发生了雄激素依赖转化．15例未发生雄激素依赖转化。采用免疫组织化学及RT—PCR法测定18例患者雄激素依赖转化前后及15例患者雄激素阻断治疗前后癌细胞内AR蛋白及AR基因的表达情况。结果：18例患者雄激素依赖转化前后AR蛋白及AR基因的表达分别为（1．33±0．97VS3．11±0．76）和（28．41±3．38Ct vs 36．73±1．81Ct）,两者之间差异有统计学意义（P〈0．01）;15例患者雄激素阻断治疗前后AR蛋白及AR基因的表达分别为（1．47±0．83 vs 1．40±0．99）和（29．50±3．08Ct vs29．14±3．23Ct）,两者之间差异无统计学意义（P〉0．05）。结论：AR基因及AR蛋白表达增强是前列腺癌雄激素依赖转化的原因之一。     

正常前列腺组织中雄激素受体亚型表达

目的 :研究雄激素受体 (AR)亚型在正常人前列腺组织中的表达及其意义。　方法 :14份正常前列腺标本均取自器官捐献者 ,年龄 2 1～ 2 8岁 ,平均 2 5岁。应用氚标技术与聚丙烯酰胺凝胶等电聚焦电泳的方法 ,对正常前列腺组织的AR亚型进行分析。　结果 :在 14份AR阳性的正常前列腺组织中发现有 4个AR亚型的表达 ,其等电点 (pI)分别为 6 .5、6 .0、5 .8和 5 .3。氚标的双氢睾酮 (DHT)与 4种受体亚型的结合 ,可以被非氚标的DHT、睾酮 (T)竞争抑制 ,而孕酮、雌二醇和己烯雌酚对此却无竞争抑制作用。　结论 :在正常人前列腺组织中 ,AR有 4个亚型表达 ,并具有因人而异的表达特征。     

雄激素受体在前列腺癌中的抗凋亡效应研究进展

前列腺癌（PCa）是中老年男性多发癌症之一，目前针对晚期转移性患者的主要治疗手段是去雄激素治疗，但是绝大部分患者最终都进展为侵袭性更强的激素非依赖型PCa，而对此类患者尚无有效治疗方法。雄激素受体（AR）是前列腺上皮细胞分化与增生的基本调节因子，在调控PCa细胞存活机制方面具有非常重要作用。目前的研究结果已经表明在激素非依赖型PCa进展过程中，AR的非正常激活是关键性因素。现简要综述AR调控的PCa细胞存活机制以及针对它而设计的RNA干扰技术对PCa的治疗运用方面的进展。     

Association among metabolic syndrome,inflammation, and survival in prostate cancer

Background

Metabolic syndrome (MS) and inflammation (INF) alterations are among the factors involved in cancer progression. The study aimed to assess the relationship between MS and INF and its effect on progression-free/overall survival (PFS/OS) in metastatic castration-resistant prostate cancer (mCRPC) treaed with abiraterone or enzalutamide.

Managing Nonmetastatic Castration-resistant Prostate Cancer

Context

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation.

AR-V7表达与去势抵抗性前列腺癌阿比特龙治疗敏感性的相关性研究

目的:探讨去势抵抗性前列腺癌(CRPC)患者中雄激素受体剪切变异体7(AR-V7)的表达与阿比特龙治疗敏感性的相关性。方法:采用前瞻性队列研究对2016年1月至2019年1月北京大学肿瘤医院收治的年龄≥18岁,存在1≥处全身转移,拟使用阿比特龙治疗的新发CRPC患者行外周血循环肿瘤细胞(CTCs)AR-V7检测,根据检测结果将患者分为AR-V7阳性组和AR-V7阴性组,对两组患者PSA下降时间、PSA无进展生存(PFS)、临床状态PFS、影像学PFS以及总生存进行统计分析。结果:共入组77例患者,其中AR-V7阴性组49例,AR-V7阳性组28例。AR-V7阴性组PSA下降时间[(72.04±66.92)d与(190.11±102.44)d,P=0.000]、PSA无应答率[6.12%(3/49)与21.4%(6/28),P=0.040]明显小于AR-V7阳性组,而PSA PFS[(489.17±269.39)d与(130.56±120)d,P=0.010]、临床状态PFS[(551.91±322.05)d与(261.44±200.85)d,P=0.018]、影像学PFS[(523.7±223.28)d与(247.56±202.80)d,P=0.003]明显长于AR-V7阳性组。AR-V7阳性组和AR-V7阴性组的肿瘤特异性生存时间分别为(1246.89±375.65)d和(1001.42±248.94)d(P=0.159),总生存率分别为89.8%(44/49)和89.3%(25/28)(P=0.176),差异均无统计学意义。结论:CRPC患者中,AR-V7表达与阿比特龙治疗敏感性及患者预后密切相关,阳性表达患者阿比特龙治疗效果及预后较差。     

苦参碱对前列腺癌细胞增殖及雄激素受体功能的抑制作用

目的:探讨苦参碱(matrine)对雄激素依赖性前列腺癌细胞株(LNCaP)的增殖及雄激素受体(androgen re-ceptor,AR)表达的抑制作用。方法:分别用0.5、1.0、1.5、2.0、3.0g/L浓度的苦参碱作用于LNCaP细胞12、24、36h后MTT法检测细胞生长活性;台盼蓝拒染法测定细胞生长曲线;24h后流式细胞仪测定细胞周期变化;24h后Western印迹法检测细胞内AR的表达。结果:苦参碱能抑制LNCaP细胞的生长,呈剂量与时间依赖性,不同浓度苦参碱组之间与不同作用时间组之间的差异均有显著性意义(P<0.01)。苦参碱诱导LNCaP细胞出现剂量依赖性G2/M期阻滞(P<0.01);细胞内AR的表达随苦参碱剂量依赖性减少(P<0.01)。结论:苦参碱通过下调细胞内AR表达和阻滞细胞周期进展来抑制LNCaP细胞的体外生长。     

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.