Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide

BackgroundAbiraterone acetate and enzalutamide both improve outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Optimal sequencing for these agents and whether cross-resistance occurs is unknown.MethodsMulticentre review of patients with mCRPC treated with abiraterone acetate and prednisone after progressing on enzalutamide. Primary objective was to determine abiraterone acetate response.ResultsThirty patients identified from four North American centres. At abiraterone initiation, median age was 70 years (56–84 years); 70% had ECOG performance status of 0–1; all had prior docetaxel. Median prior enzalutamide treatment duration was 41 weeks (6–95 weeks), with 70% (21 of 30) having a ≥30% prostate-specific antigen (PSA) decline. Median abiraterone acetate treatment duration was 13 weeks (1–52). No objective radiographic responses were observed. Median abiraterone time to progression (PSA, objective or symptomatic) was 15.4 weeks [95% confidence interval (CI) 10.7–20.2]. Median overall survival was 50.1 weeks (95% CI 28.3–72.0). Three patients had a ≥30% PSA decline with abiraterone. Two of these patients had PSA progression as best response with prior enzalutamide.ConclusionsIn this study of patients progressing after enzalutamide, treatment with abiraterone was associated with a modest response rate and brief duration of effect. Primary progression on enzalutamide may not preclude a response to abiraterone.     

Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100)

BackgroundAndrogen receptor (AR) signalling remains critically important in metastatic castration-resistant prostate cancer (mCRPC) as confirmed by recent phase III trials, showing a survival advantage for abiraterone acetate and enzalutamide (MDV3100). The antitumour activity of abiraterone and prednisolone in patients pre-treated with enzalutamide is as yet unknown.Patients and methodsWe investigated the antitumour activity of abiraterone and prednisolone in patients with mCRPC who had progressed following treatment with docetaxel (Taxotere) and enzalutamide. Clinical data were retrospectively analysed for prostate-specific antigen (PSA) and RECIST responses, clinical benefit and survival.ResultsThirty-eight patients were included in the analysis. The median age was 71 years (range 52–84); metastatic sites included bone disease in 37 patients (97%), lymph nodes in 15 patients (39%) and visceral disease in 10 patients (26%). Abiraterone was well tolerated. Three patients (8%) attained a PSA response, defined as ≥50% decline in PSA confirmed after ≥4 weeks, while seven patients (18%) had a ≥30% PSA decline. The median progression-free survival (PFS) was 2.7 months (95% CI 2.3–4.1). Of the 12 patients assessable radiologically, only 1 (8%) attained a confirmed partial response.ConclusionAbiraterone and prednisolone have modest antitumour activities in patients with mCRPC pretreated with docetaxel and enzalutamide.     

Effect of abiraterone acetate on fatigue in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy

BackgroundFatigue is a common, debilitating side-effect of prostate cancer and its treatment. Patient-reported fatigue was evaluated as part of COU-AA-301, a randomized, placebo-controlled, phase III trial of abiraterone acetate and prednisone versus placebo and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel chemotherapy. This is the first phase III study in advanced prostate cancer to evaluate fatigue outcomes using a validated fatigue-specific instrument.Patients and methodsThe Brief Fatigue Inventory (BFI) questionnaire was used to measure patient-reported fatigue intensity and fatigue interference with activities of daily life. All analyses were conducted using prespecified responder definitions of clinically meaningful changes.ResultsA total of 797 patients were randomized to abiraterone acetate and prednisone, and 398 were randomized to placebo and prednisone. Compared with prednisone alone, in patients with clinically significant fatigue at baseline, abiraterone acetate and prednisone significantly increased the proportion of patients reporting improvement in fatigue intensity (58.1% versus 40.3%, P = 0.0001), improved fatigue interference (55.0% versus 38.0%, P = 0.0075), and accelerated improvement in fatigue intensity (median 59 days versus 194 days, P = 0.0155).ConclusionsIn patients with mCRPC progressing after docetaxel chemotherapy, abiraterone acetate and prednisone yielded clinically meaningful improvements in patient-reported fatigue compared with prednisone alone.     

Therapeutic options for first-line metastatic castration-resistant prostate cancer: Suggestions for clinical practise in the CHAARTED and LATITUDE era

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.     

Impact of prior androgen receptor-axis-targeted agents on the clinical activity of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer: comparative assessment between abiraterone acetate and enzalutamide

The objective of this study was to investigate the impact of prior treatment with androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate (AA) and enzalutamide (Enz), on the activity of subsequently introduced docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 114 mCRPC patients consisting of 54 and 60 who progressed following treatment with AA and Enz, respectively, prior to the introduction of docetaxel, and compared oncological outcomes with docetaxel between these two groups. There were no significant differences in the major clinicopathological characteristics before treatment with docetaxel between the AA and Enz groups. The prostate-specific antigen (PSA) response rates to docetaxel in the AA and Enz groups were 40.7 and 43.3%, respectively, with no significant differences in the rates between these two groups. Following the introduction of docetaxel, the median PSA progression-free survival (PFS) and overall survival (OS) in the 114 patients were 7.2 and 17.5 months, respectively. There was no significant difference in the PSA PFS or OS between the AA and Enz groups. Despite the lack of a significant impact of the type of ARAT agent on PSA PFS or OS by univariate analysis, multivariate analyses identified the following independent prognostic predictors: performance status (PS) for PSA PFS and PS and visceral metastasis for OS. Collectively, these findings suggest that the type of ARAT agent may not have a significant impact on disease control by subsequent docetaxel therapy in mCRPC patients.     

Systemic Therapy in Men with Metastatic Castration-resistant Prostate Cancer: A Systematic Review

AimsSince 2004, docetaxel-based chemotherapy has been the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), but recently randomised controlled trials (RCTs) of novel agents have shown promise in extending overall survival. These trials have evaluated agents delivered before chemotherapy, to replace or supplement docetaxel, or addressed treatment options for men who have progressed on docetaxel therapy. This review was undertaken to determine which systemic therapies improve cancer- or patient-related outcomes in men with mCRPC.Materials and methodsSearches were carried out in MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. Eligible articles included RCTs comparing systemic therapy or combination (excluding primary or secondary androgen deprivation therapy, bone protective agents or radionuclides) with placebo or other agents in men with mCRPC.ResultsTwenty-five RCTs met the selection criteria. In chemotherapy-naive patients, targeted therapy with tasquinimod conferred a benefit in progression-free survival. Immunotherapy with sipuleucel-T extended overall survival and was well tolerated, but had no effect on the time to disease progression. Hypercastration with abiraterone extended progression-free survival, whereas overall survival was improved but not statistically proven. In the chemotherapy setting, updated and new trials of docetaxel alone confirmed the survival benefit seen in previous studies. A survival benefit with the addition of estramustine to docetaxel shown in a previous study did not lead to an improvement in pain palliation or quality of life. Trials of combining targeted therapies with docetaxel generally did not extend survival. The addition of bevacizumab improved progression-free survival, but not overall survival. The addition of GVAX immunotherapy or calcitriol was harmful. In the post-chemotherapy setting, progression-free and overall survival benefits were detected with cabazitaxel, abiraterone and enzalutamide. Cabazitaxel was associated with greater toxicity, whereas abiraterone and enzalutamide had less severe adverse effects. Satraplatin and sunitinib both extended progression-free survival, but did not improve overall survival.ConclusionDocetaxel-based chemotherapy remains the standard of care in men with mCRPC who are candidates for palliative systemic therapy. Promising results are emerging with sipuleucel-T and abiraterone in the pre-docetaxel setting and cabazitaxel, abiraterone and enzalutamide in patients who progress on or after docetaxel. Further research to determine the optimal choice, sequence or even the combination of these agents is necessary.     

Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance?

BackgroundAbiraterone and docetaxel are both approved treatments for men with metastatic castration-resistant prostate cancer (mCRPC). Abiraterone pre-docetaxel is currently undergoing evaluation in a phase III study. In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling. We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy.Patients and methodsWe retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone, using Prostate Cancer Working Group and radiological criteria.ResultsOf the 54 patients treated with abiraterone, 35 subsequently received docetaxel. Docetaxel resulted in a prostate-specific antigen (PSA) decline of ≥50% in nine patients [26%, 95% confidence interval (CI) 13% to 43%], with a median time to PSA progression of 4.6 months (95% CI 4.2% to 5.9%). PSA declines ≥30% were achieved by 13 patients (37%, 95% CI 22% to 55%). The median overall survival was 12.5 months (95% CI 10.6–19.4). All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone-refractory were also docetaxel-refractory (N = 8). In the 24 patients with radiologically evaluable disease, partial responses were reported in four patients (11%), none of whom were abiraterone-refractory.ConclusionThe activity of docetaxel post-abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone-refractory patients.     

Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer

IntroductionTreatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1]. In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds.MethodsTo identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation.ResultsWe observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide.ConclusionsIn conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.     

多西他赛再挑战治疗转移性去势抵抗性前列腺癌的疗效及预后因素

目的 评价多西他赛再挑战治疗一线多西他赛治疗有效的转移性去势抵抗性前列腺癌（mCRPC）患者的疗效，并分析预后因素。方法 回顾性分析120例mCRPC患者的临床资料，观察终点为第一序列多西他赛化疗后前列腺特异性抗原无疾病进展生存期（PSA PFS）和多西他赛再挑战后前列腺特异性抗原无疾病进展生存期（Rechallenge PSA PFS）以及mCRPC患者总生存期（OS）。采用Cox单因素和多因素回归模型对患者PSA PFS、Rechallenge PSA PFS和OS相关的预后因素进行分析。结果 中位随访时间32.73（13.27~98.56）月，30例（25%）患者仍存活。中位PSA PFS 13.89（7.67~39.00）月，中位Rechallenge PSA PFS 5.29（1.25~20.00）月，中位OS 27.13（12.40~60.50）月。多因素回归分析显示：第一序列多西他赛化疗与多西他赛再挑战之间的治疗间歇期（>6月vs.≤6月）与患者的PSA PFS显著相关，对多西他赛再挑战治疗反应性（获得部分反应vs.未获得部分反应）与Rechallenge PSA PFS显著相关，mCRPC患者就诊时基础血清PSA值及对多西他赛再挑战治疗反应性（获得部分反应vs.未获得部分反应）与OS显著相关。结论 多西他赛在一线使用多西他赛有效的mCRPC患者中再次使用疗效尚可，可作为此类患者后期治疗的一种选择。     

Résistance au docétaxel: mécanismes et applications thérapeutiques

Docetaxel is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients, but its effectiveness is limited in time and tumor escape the inevitable. The various combinations with docetaxel were negative in terms of prolongation of overall survival. A better understanding of mechanisms of docetaxel resistance on microtubule and p-glycoprotein, for instance, would guide the therapeutic strategy. After the administration of docetaxel, cabazitaxel, abiraterone, alpharadin and recently MDV3100 have shown their effectiveness in improving overall survival compared to a placebo or mitoxantrone in phase III trials. Also in predocetaxel stage, sipuleucel-T has proven effective in asymptomatic mCRPC patients. The identification of predictors of response to taxanes will personalize chemotherapy to induce durable response and significantly prolonged survival.     

Emerging and second line therapies for the management of metastatic castration-resistant prostate cancer: the Australian perspective

Since the establishment of docetaxel as first-line chemotherapy for metastatic castration-resistant prostate cancer significant advancements have been made in the management of this disease. Clinical trials have investigated agents for use prior to docetaxel, in combination with docetaxel and agents for second-line treatment for patients who have progressed despite docetaxel. In addition, several new agents have been developed and clinically investigated in the fields of hormonal, cytotoxic, targeted and immune therapy, providing options either side of first-line chemotherapy. As a result of this considerable research activity, three new therapies; cabazitaxel, sipuleucel-T and abiraterone acetate, have each demonstrated improvement in overall survival in phase III trials and have been approved by the US Food and Drug Administration. With so many new therapies now available and in the pipeline, the management of metastatic castration-resistant prostate cancer is undergoing a significant and positive change. This article discusses current and future options for second-line therapy in metastatic castration-resistant prostate cancer, providing insight into the potential roles of these new treatment options in the Australian clinical setting.     

Pleuropulmonary and Lymph Node Progression after Docetaxel – Benefits from Treatment with Cabazitaxel in Metastatic Prostate Cancer

Introduction

To date, there are no guidelines for a rational and more favourable sequence of treatment after docetaxel. Two drugs (cabazitaxel and abiraterone) have recently been approved as second-line treatment after docetaxel failure in metastatic castration-resistant prostate cancer (mCRPC), but there are no studies comparing abiraterone versus cabazitaxel. The most suitable drug is chosen based on the physician''s opinion and the patient''s characteristics. In patients with a good performance status who are able to receive either treatment, it would be convenient to begin with cabazitaxel and to reserve abiraterone in case there is a worsening of the general status, in consideration of abiraterone''s more favourable toxicity profile.

Case Report

We describe the case of a 74-year-old male with mCRPC who presented with an interesting and uncommon tumour dissemination (pleuropulmonary) occurring after the first standard treatment with docetaxel. Intravenous treatment with cabazitaxel 25 mg/m² and oral prednisone 10 mg continuously was initiated. The patient received a total of 8 cycles of chemotherapy. A reduction of mediastinal adenopathies and infrarenal para-aortic stable bone involvement and an absence of pleural effusion were observed. No relevant toxicity was noted. Since February 2012, a progressive PSA increase without clinical deterioration has been noted.

Conclusions

The selection criteria for second- and third-line systemic treatment and the excellent response obtained with cabazitaxel in an unusual disease setting are described. The results confirm the long duration and quality of response of cabazitaxel treatment. Further therapeutic options in this group of patients are suggested.Key words: Cabazitaxel, Castration-resistant prostate cancer, Pleuropulmonary progression     

Safety and Efficacy of Maintenance Therapy With a Nonspecific Cytochrome P17 Inhibitor (CYP17i) After Response/Stabilization to Docetaxel in Metastatic Castration-Resistant Prostate Cancer

BackgroundFrontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored.MethodsWe identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing–hormone agonists (LHRHa) and who were treated with a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m²) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa, whereas 10 patients received LHRHa alone. TTP was the primary endpoint.ResultsAfter a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism.ConclusionThis is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.     

Medical strategies for treatment of castration resistant prostate cancer (CRPC) docetaxel resistant

Current landscape of treatment of castration-resistant prostate cancer (CRPC) has recently changed. Cabazitaxel, a new taxane with potential antineoplastic activity, has been approved by Food and Drug Administration (FDA) after docetaxel failure. In a phase III trial, cabazitaxel showed increased overall survival (OS) compared with mitoxantrone (15.1 vs. 12.7 mo, HR 0.70, 95% CI 0.59-0.83, p < 0.0001). Furthermore, chemotherapy is not the only strategy available: several studies have shown as CRPC remains dependent on androgen receptor function for growth. Abiraterone acetate, an irreversible inhibitor of CYP17, has also been approved by FDA after docetaxel failure. In a phase III trial comparing abiraterone acetate to placebo, abiraterone showed improvement in OS (14.8 vs. 10.4 mo, HR 0.65, 95% CI 0.54-0.77; p < 0.0001). This review will discuss current options and the ongoing trials for second-line treatment of CRPC including chemotherapy, hormonal therapies, antiangiogenetic and immune strategies.     

CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate‐resistant prostate cancer previously treated with docetaxel

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.     

Impact of an alternative steroid on the relative bioavailability and bioequivalence of a novel versus the originator formulation of abiraterone acetate

Cancer Chemotherapy and Pharmacology - The originator abiraterone acetate (OAA) formulation is used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study...     

Broadening horizons in medical management of prostate cancer

HORMONAL THERAPY: Testosterone suppression achieved either medically or surgically is the standard initial treatment for men with advanced prostate cancer. Most men respond but the disease progresses after a median of 1-2 years. Clinical trials suggest that intermittent androgen deprivation therapy (ADT) provides equal or longer time to castration-independence than continuous ADT, and is preferred, especially since there are subtle long-term toxicities associated with ADT. Further hormonal manipulations (including addition and withdrawal of peripheral antiandrogens, steroid synthesis inhibitors such as ketoconazole, and estrogens) can be transiently effective in selected patients with castration-resistant prostate cancer (CRPC). Androgen-dependent signalling pathways remain active in most men with CRPC and are associated with mutation, changes in expression or modulation of the androgen receptor (AR); abiraterone acetate and MDV3100 are promising drugs being evaluated in clinical trials that may lead to further hormonal response. CHEMOTHERAPY: Eventually men who progress rapidly, are symptomatic, and/or develop metastasis to visceral organs require chemotherapy. Three-weekly docetaxel with prednisone has been shown to improve survival and relieve symptoms but eventually men develop progressive disease or become intolerant to docetaxel. Multiple trials are evaluating new drugs (mainly molecular targeted agents) either given first line with docetaxel chemotherapy, or to men who have progressive disease after receiving docetaxel. Cabazitaxel was shown recently to improve survival as compared to mitoxantrone when used second line and has been approved by the United States Food and Drug Administration (FDA). CONCLUSION: Despite major advances, treatment of men with advanced CRPC remains a challenge both for the seeker and giver of care.     

多西他赛联合醋酸甲羟孕酮片治疗转移性去势抵抗性前列腺癌的临床疗效观察

目的:探讨多西他赛联合醋酸甲羟孕酮片（MAD）治疗转移性去势抵抗性前列腺癌（mCRPC）的临床疗效。方法:收集2013年12月至2016年6月我科收治的转移性去势抵抗性前列腺癌患者64例，随机分为对照组和观察组，每组32例。对照组接受多西他赛联合强的松治疗，观察组在对照组的基础上联合服用醋酸甲羟孕酮片。评价治疗后两组患者前列腺特异性抗原（PSA）有效率、碱性磷酸酶（ALP）下降率、不良反应、无疾病进展生存时间（PFS）和总生存时间（OS）的差异。结果:化疗结束后，观察组的PSA有效率和ALP下降率分别为96.9%和46.9%，对照组分别为90.6%和56.3%，组间比较无统计学意义（P>0.05）。全组患者白细胞下降发生率为100%，观察组Ⅲ-Ⅳ度白细胞和血红蛋白下降率、Ⅱ度乏力发生率均低于对照组，组间比较具有统计学差异（P＜0.05）。观察组和对照组的PFS分别9.6个月和10.0个月，OS分别为19.3个月和18.6个月，组间PFS和OS比较无统计学差异（P>0.05）。结论:多西他赛治疗mCRPC患者的主要不良反应为白细胞下降，联合使用醋酸甲羟孕酮片可有效改善化疗不良反应。     

AR-V7 and prostate cancer: The watershed for treatment selection?

The androgen receptor (AR) plays a key role in progression to metastatic castration-resistant prostate cancer (mCRPC). Despite the recent progress in targeting persistent AR activity with the next-generation hormonal therapies (abiraterone acetate and enzalutamide), resistance to these agents limits therapeutic efficacy for many patients. Several explanations for response and/or resistance to abiraterone acetate and enzalutamide are emerging, but growing interest is focusing on importance of AR splice variants (AR-Vs) and in particular of AR-V7. Increasing evidences highlight the concept that variant expression could be used as a potential predictive biomarker and a therapeutic target in advanced prostate cancer. Therefore, understanding the mechanisms of treatment resistance or sensitivity can help to achieve a more effective management of mCRPC, increasing clinical outcomes and representing a promising and engaging area of prostate cancer research.     

Beyond Frontline Therapy with Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer: A Real-World US Study

BackgroundReal-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L+). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting.MethodsAdults with confirmed adenocarcinoma mCRPC diagnosis and ≥1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013–03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis.ResultsAmong 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC (>75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone → 2L enzalutamide → 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively.ConclusionsThis real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.