Recent trend of androgen deprivation therapy in newly diagnosed prostate cancer patients: Comparing between high- and middle-income Asian countries

The number of newly diagnosed prostate cancer cases varies across Asia, with higher mortality-to-incidence ratio reported in developing nations. Androgen deprivation therapy (ADT), alone or in combination, remains the mainstay of first-line treatment for advanced prostate cancer. Key findings of extensive research and randomized controlled trials have shaped current clinical practice and influenced clinical guideline recommendations. We describe here the recent trend of ADT in newly diagnosed prostate cancer for Asia focusing on Japan (high-income country) and Malaysia (middle-income country) based on the Asian Prostate Cancer (A-CaP) Study. The combination of radiotherapy and ADT or ADT alone was common in patients with intermediate-to-high risk localized and locally advanced disease. For metastatic prostate cancer, maximum androgen blockade (gonadotrophin-releasing hormone [GnRH] agonist/antagonist plus antiandrogen) was prevalent among the Japanese patients while primary ADT alone with GnRH agonist/antagonist was widely practiced in the Malaysian cohort. Upfront combined therapy (ADT plus docetaxel or androgen receptor pathway inhibitor) has significantly improved the outcomes of patients with metastatic castration-naïve prostate cancer. Its application, however, remains low in our cohorts due to patients’ financial capacity and national health insurance coverage. Early detection remains the cornerstone in prostate cancer control to improve treatment outcome and patient survival.     

Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer

After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer.     

Androgen metabolism in prostate cancer: from molecular mechanisms to clinical consequences

Despite our most vigorous efforts, prostate cancer remains the second leading cause of cancer death in men. Understanding the intricacies of androgen metabolism is vital to finding therapeutic targets, particularly with progression of advanced prostate cancer after initial hormone therapy, where adrenal precursors are involved. Such is the case with castration-resistant prostate cancer, where adrenal androgens, for example, dehydroepiandrosterone, are a source for intratumoural synthesis of dihydrotestosterone. As prostate cancer progresses, androgen metabolism changes due to altered expression of steroidogenic enzymes and mutations in the components of the steroidogenic machinery. These alterations sustain disease and allow progression; mechanistically, they may also enable development of hormone therapy resistance. With the development of the newer agents, abiraterone acetate and enzalutamide, efforts have been made to better define the basis for response and resistance. This work can be carried out in cell lines, animal models, as well as with ex vivo analysis of tissues obtained from patients. Efforts to further elucidate the finer details of the steroidogenic pathway are necessary to move toward a curative paradigm for patients with localised disease at high risk for recurrence.     

Collateral resistance to taxanes in enzalutamide‐resistant prostate cancer through aberrant androgen receptor and its variants

Currently, the optimal sequential use of androgen receptor (AR) axis‐targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide‐resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane‐resistant cells showed no collateral resistance to enzalutamide; taxane‐resistant cells expressed comparable protein levels of full‐length AR and AR variants. Knockdown of both full‐length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full‐length AR rendered cells resistant to taxanes. Consistently, the prostate‐specific antigen response and progression‐free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.     

Metastatic castration-resistant prostate cancer: targeting the mechanisms of resistance to abiraterone acetate and enzalutamide

Persistent androgen receptor (AR) axis is a functionally important pathway for prostate cancer cells and it is currently regarded as a critical therapeutic target. Although the impressive clinical activity of new hormonal agents, such as the second-generation AR antagonist enzalutamide (formerly MDV3100) and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone acetate (AA), in patients with metastatic castration-resistant prostate cancer (mCRPC), innate or acquired resistance invariably arises. To date, emerging hypotheses are different, but the mechanisms of resistance to these drugs have not yet been clarified. The aim of this review is to summarize the main data available on the evaluation of the multiple levels of development of resistance to next-generation AR-directed therapies. Understanding how the AR is activated may have clinical implications in defining which patients will respond to existing therapeutic agents and provide a proof for making novel strategies.     

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT‐resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT‐resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox‐induced overexpression of any Notch intracellular domains (NICD1‐4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance‐associated phospho‐p38 and Bcl‐2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using γ‐secretase inhibitor (GSI), DAPT, downregulated both phospho‐p38 and Bcl‐2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa.     

Challenges in the sequencing of therapies for the management of metastatic castration‐resistant prostate cancer

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration‐resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel‐T) and radium‐233 (for symptomatic bone metastases). With several other agents in the pipeline for late‐stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient‐focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.     

同期调强放疗联合内分泌治疗对局部晚期前列腺癌患者免疫指标的影响

目的:探讨同期调强放疗联合内分泌治疗对局部晚期前列腺癌患者机体免疫指标的影响.方法:92例局部晚期前列腺癌患者纳入研究,随机分为内分泌治疗(androgen deprivation therapy,ADT)组和放疗联合内分泌治疗(radiotherapy plus androgen deprivation therapy,RT+ ADT)组,ADT组方案:口服比卡鲁胺片50mg/次,1次/d,皮下注射醋酸戈舍瑞林3.6mg/次,1次/28d;RT+ ADT组方案:肿瘤体积靶区2.2Gy/f,1次/d,每周5次,共31次,前列腺病灶肿瘤剂量68.2Gy.采用酶联免疫吸附法,分别比较健康人群与内分泌治疗组、放疗联合内分泌治疗组治疗前和治疗后T淋巴细胞亚群(CD3+、CD4+、CD8+、CD4 +/CD8+)和NK细胞二者的差异.结果:健康对照组CD3+、CD4+、CD8+均高于ADT组和RT+ ADT组基线评价和治疗后,且有统计学差异(P＜0.05);ADT组和RT+ ADT组治疗后CD3+、CD4+、CD8+较基线评价均有不同程度升高,且二者比较有统计学差异(P＜0.05);RT+ ADT组在治疗结束后CD3+、CD4+、CD4+/CD8+均高于ADT组,有统计学差异(P＜0.05);CD8+低于ADT组,差异有统计学意义(P＜0.05).结论:局部晚期前列腺癌患者存在不同程度的免疫功能紊乱,同期调强放射联合内分泌治疗可在近期内改善局部晚期前列腺癌患者的免疫功能.     

Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy

Upregulation of constitutively-active androgen receptor splice variants (AR-Vs) has been implicated in AR-driven tumor progression in castration-resistant prostate cancer. To date, functional studies of AR-Vs have been focused mainly on their ability to regulate gene expression independent of the full-length AR (AR-FL). Here, we showed that AR-V7 and AR^v567es, two major AR-Vs, both facilitated AR-FL nuclear localization in the absence of androgen and mitigated the ability of the antiandrogen enzalutamide to inhibit AR-FL nuclear trafficking. AR-V bound to the promoter of its specific target without AR-FL, but co-occupied the promoter of canonical AR target with AR-FL in a mutually-dependent manner. AR-V expression attenuated both androgen and enzalutamide modulation of AR-FL activity/cell growth, and mitigated the in vivo antitumor efficacy of enzalutamide. Furthermore, AR^v567es levels were upregulated in xenograft tumors that had acquired enzalutamide resistance. Collectively, this study highlights a dual function of AR-Vs in mediating castration resistance. In addition to trans-activating target genes independent of AR-FL, AR-Vs can serve as a “rheostat” to control the degree of response of AR-FL to androgen-directed therapy via activating AR-FL in an androgen-independent manner. The findings shed new insights into the mechanisms of AR-V-mediated castration resistance and have significant therapeutic implications.     

Downregulation of lysine-specific demethylase 1 enhances the sensitivity of hormone-sensitive prostate cancer cells to androgen deprivation therapy

Lysine-specific demethylase 1 (LSD1) plays an important role in androgen receptor (AR) signaling, and LSD1 levels are associated with prostate cancer (PCa) progression. The present study investigated the association between the downregulation of LSD1 and the proliferation and invasiveness of PCa cells, as well as the effect of LSD1 on the androgen deprivation therapy (ADT)-induced apoptosis of PCa cells. The effect of the inhibition of LSD1 combined with ADT on PCa cell apoptosis was characterized. Furthermore, the mechanisms underlying LSD1-mediated apoptosis induced by ADT in PCa cells were investigated. Downregulation of LSD1 impaired the proliferation and invasiveness of PCa cells. Moreover, downregulation of LSD1 enhanced the apoptosis of PCa cells induced by bicalutamide in vitro. Downregulation of LSD1 decreased PSA expression, increased caspase 3 and Bax expression, decreased Bcl-2 expression and consequently enhanced castration-induced PCa cell apoptosis in vivo. These findings indicated that downregulation of LSD1 could effectively enhance the efficacy of ADT for hormone- sensitive PCa, demonstrating that this could be a promising adjunctive therapy with ADT for this disease.     

Quo vadis: Advanced prostate cancer—clinical care and clinical research in the era of multiple androgen receptor‐directed therapies

The novel androgen receptor‐directed therapies abiraterone acetate and enzalutamide, having demonstrated improved survival in randomized phase 3 studies of men with metastatic castration‐resistant prostate cancer, have ushered in a new era in the treatment of this disease. Additional novel androgen receptor‐directed therapies, such as ARN‐509 and orteronel, are in various phases of clinical trials and development. However, the emergence of therapeutic resistance and clinical disease progression is inevitable. Although advances in genomic technologies have led to unprecedented understanding of the biology of castration‐resistant prostate cancer, efforts only now are underway to elucidate the mechanisms of resistance associated with abiraterone and enzalutamide. A tremendous challenge in the near future will be to determine the optimal sequence or combination of therapies to overcome resistance mechanisms. In this review, the current landscape of androgen receptor‐directed therapies and future directions necessary to enhance their clinical efficacy for the maximal benefit of patients are discussed. Cancer 2015;121:361–371. © 2014 American Cancer Society.     

Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer

BACKGROUND: The use of androgen deprivation therapy (ADT) in the treatment of men with prostate cancer has risen sharply. Although cardiovascular disease is the most common reason for death among men with prostate cancer who do not die of the disease itself, data regarding the effect of ADT on cardiovascular morbidity and mortality in men with prostate cancer are limited. In the current study, the authors attempted to measure the risk for subsequent cardiovascular morbidity in men with prostate cancer who received ADT. METHODS: A cohort of newly diagnosed men in a population-based registry who were diagnosed between 1992 and 1996 were identified retrospectively. A total of 22,816 subjects were identified after exclusion criteria were applied. Using a multivariate model, the authors calculated the risk of subsequent cardiovascular morbidity in men with prostate cancer who were treated with ADT, as defined using Medicare claims. RESULTS: Newly diagnosed prostate cancer patients who received ADT for at least 1 year were found to have a 20% higher risk of serious cardiovascular morbidity compared with similar men who did not receive ADT. Subjects began incurring this higher risk within 12 months of treatment. However, Hispanic men were found to have a lowered risk for cardiovascular morbidity. CONCLUSIONS: ADT is associated with significantly increased cardiovascular morbidity in men with prostate cancer and may lower overall survival in men with low-risk disease. These data have particular relevance to decisions regarding the use of ADT in men with prostate cancer in settings in which the benefit has not been clearly established. For men with metastatic disease, focused efforts to reduce cardiac risk factors through diet, exercise, or the use of lipid-lowering agents may mitigate some of the risks of ADT.     

Sleep and daily functioning during androgen deprivation therapy for prostate cancer

HANISCH L.J., GOONERATNE N.S., SOIN K., GEHRMAN P.R., VAUGHN D.J. & COYNE J.C. (2010) European Journal of Cancer Care
Sleep and daily functioning during androgen deprivation therapy for prostate cancer A limited body of evidence suggests that sleep problems are common in prostate cancer patients undergoing androgen deprivation therapy, yet little is known about sleep characteristics and the effects of poor sleep on daily functioning in this population. This study assessed sleep in 60 prostate cancer patients taking androgen deprivation therapy with wrist actigraphy and daily diaries for 7 days. The Epworth Sleepiness Scale and the general version of the Functional Assessment of Cancer Therapy scale were also administered. On average, total sleep time was 5.9 (SD = 1.4) h, and sleep efficiency was 75% (SD = 12.0) as assessed by actigraphy. There was generally poor concordance between actigraphy and daily diary for most sleep metrics. Subjects reported awakening, on average, 2.7 times per night, most commonly for nocturia and hot flashes. Assessment of daily functioning showed that participants had mild daytime sleepiness, which was predicted by total sleep time (F(1,47) = 4.5, P= 0.04) General quality of life was not impaired. This study supports more research on the predictors of poor sleep in order to identify effective interventions.     

雄激素受体在前列腺癌细胞中作用及其靶向治疗的研究进展

雄激素受体(androgen receptor, AR)在前列腺癌的发生发展中扮演重要角色。雄激素剥夺疗法(androgen deprivationtherapy, ADT)早期可成功抑制肿瘤的生长, 但最终导致肿瘤复发并进入激素抵抗阶段。AR对前列腺癌基质细胞起促进肿瘤增殖和转移作用, 是上皮腔样细胞的存活因子, 而对肿瘤干细胞样细胞及上皮基底细胞的增殖起抑制作用, AR在不同类型细胞中的不同作用向当前ADT传统的疗法提出挑战, 为发展新的治疗策略提供理论依据。目前以AR为靶点的靶向治疗药物研发也取得一些进展。本文就AR在前列腺癌不同类型细胞中的作用及靶向治疗方面的进展加以综述。      

Zoledronic acid to prevent bone loss in Chinese men receiving androgen deprivation therapy for prostate cancer

Aim: To explore the bone mineral density (BMD) preservation effect of zoledronic acid and its renal safety and tolerability in Chinese patients with prostate cancer on androgen deprivation therapy (ADT). Methods: Overall 26 prostate cancer patients with ADT were given zoledronic acid 4 mg by a 15‐min i.v. infusion every 3 months for up to 12 months. Assessment was made at baseline and at 3, 6, 9 and 12 months. Dual‐energy X‐ray absorptiometry was used to measure the BMD of the lumbar spine and the femoral neck at baseline and 12 months. Results: A total of 23 of 26 recruited patients completed the study. Seven patients had bone metastases. The overall mean increase in BMD (T‐score) of the lumbar spine and femoral head from baseline to follow up at 12 months was significant (−2.32 ± 0.98 to −2.03 ± 1.08, P = 0.02 and −1.77 ± 0.72 to −1.63 ± 0.76, P = 0.01, respectively). In subgroup analyses, significant BMD improvement was observed independent of the status of bone metastasis and the means of ADT. Zoledronic acid had no adverse effect on renal function. Adverse events related to zoledronic acid were minimal. Conclusion: Zoledronic acid administered every 3 months significantly increased BMD in prostate cancer patients receiving ADT. It had a satisfactory adverse event profile and imposed minimal risk on patients' renal function.