Chemotherapy for metastatic castration‐sensitive prostate cancer

Incorporation of docetaxel into metastatic castration‐sensitive prostate cancer treatment has added a new treatment option to a disease state that had previously not seen change for decades. Early attempts of a chemo‐hormonal approach for castration‐sensitive prostate cancer were not successful. With the demonstration of survival benefits using docetaxel in patients with metastatic castration‐resistant prostate cancer, this encouraged continued research with docetaxel given earlier in the disease course. Three randomized phase III trials have defined the benefits of docetaxel in the metastatic castration‐sensitive prostate cancer setting; however, there remain questions and controversies on the appropriate and optimal patient selection.     

Novel agents for castration‐resistant prostate cancer: Early experience and beyond

Androgen deprivation therapy is the initial treatment for men with advanced prostate cancer. Almost all these patients eventually develop progressive castration‐resistant prostate cancer despite an initial favorable response. Docetaxel was the first agent to show a survival benefit in patients with castration‐resistant prostate cancer. After cancer progression on docetaxel, patients with castration‐resistant prostate cancer had few therapeutic options. A better understanding of the mechanisms of resistance to androgen deprivation therapy has led to the development of novel agents with distinct mechanisms of action. Prospective, large‐scale clinical trials have shown overall survival benefits with the hormonal agents abiraterone acetate and enzalutamide, the immunotherapeutic agent sipuleucel T, the chemotherapeutic agent cabazitaxel, and bone‐targeted Ra‐223. Although these agents provided clinical benefit, treatment for castration‐resistant prostate cancer remains a major clinical challenge. We recognize many questions, such as methods to select patients for specific treatments, optimal sequencing and drug combinations, and means to overcome drug resistance. There is an urgent need to answer these questions and to establish better treatment strategies. The development of biomarkers that are predictive of treatment results is also required. The present article reviews new castration‐resistant prostate cancer treatments, and discusses possible resistant mechanisms as well as potential drug combinations and optimal sequencing.     

Therapies for castration‐resistant prostate cancer in a new era: The indication of vintage hormonal therapy,chemotherapy and the new medicines

When advanced prostate cancer recurred during hormonal therapy and became the castration‐resistant prostate cancer, “vintage hormonal therapy,” such as antiandrogen alternating therapy or estrogen‐related hormonal therapy, was widely carried out in Japan until 2013. This vintage hormonal therapy controlled the progression of castration‐resistant prostate cancer. When castration‐resistant prostate cancer relapses during these therapies, chemotherapy using docetaxel has been carried out subsequently. Since new hormonal therapies using abiraterone acetate and enzalutamide, which improve the prognosis of castration‐resistant prostate cancer, became available in Japan from 2014, therapeutic options for castration‐resistant prostate cancer have increased. Furthermore, the improvement of the further prognosis is promising by using cabazitaxel for docetaxel‐resistant castration‐resistant prostate cancer and radium‐223 for castration‐resistant prostate cancer with bone metastasis. An increase in therapeutic options gives rise to many questions, including best timing to use them and the indication. Furthermore, physicians have to consider the treatment for the recurrence after having carried out chemotherapy. We want to argue the difference in hormonal therapy between Japan and Western countries, and problems when carrying out new treatments, and the importance of imaging in the present review article.     

Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone‐sensitive prostate cancer

Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone‐sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer‐related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone‐sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor‐targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration‐resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone‐sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone‐sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor‐targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone‐sensitive prostate cancer, and discusses future perspectives in this field.     

Impact of docetaxel-based chemotherapy on quality of life of patients with castration-resistant prostate cancer: results from a prospective phase II randomized trial

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Data on quality of life during docetaxel treatment in castration resistant prostate cancer was mainly provided by SWOG and TAX327 trials. In the TAX327 trial biochemical response and pain predicted survival, whereas quality of life outcomes did not. In the present study, there were no statistically significant changes in the quality of life scales during treatment except in the case of patients receiving docetaxel and estramustine, who experienced a significant decrease in pain. Our data seem to suggest that patients with a better baseline quality of life (and consequently with fewer symptoms) are more likely to achieve a biochemical response.

OBJECTIVES

? To assess quality of life (QoL) outcomes and pain changes in patients affected by castration‐resistant prostate cancer enrolled in a phase II randomized trial of 3‐week docetaxel (DOC)‐based chemotherapy. ? To provide further data to clarify the conflicting published data concerning the impact of DOC on the patients’ QoL.

PATIENTS AND METHODS

? QoL outcomes were assessed using the European Organisation for the Research and Treatment of Cancer QLQ‐C30 questionnaire. ? Pain changes were evaluated by means of the Brief Pain Inventory at baseline and after every two DOC courses. ? The patients completing at least two questionnaires (at baseline and before the third course) were considered evaluable.

RESULTS

? In all, 59 patients were evaluable. ? Asymptomatic patients and responders had a better baseline QoL than symptomatic patients and non‐responders. ? There were no statistically significant changes in the QLQ‐C30 scales during treatment except in the case of patients receiving DOC and estramustine, who experienced a significant decrease in pain. ? There was a progressive improvement in the mean intensity and interference scores of the Brief Pain Inventory.

CONCLUSIONS

? Our data confirm that QoL is generally maintained during chemotherapy. ? There is a substantial reduction in pain. ? Our results also suggest that baseline QoL may predict treatment response.     

Influence of prior oral ethinylestradiol use on the efficacy of enzalutamide for the treatment of castration‐resistant prostate cancer in men

Objective

To elucidate the effect of prior use of ethinylestradiol on enzalutamide treatment for men with castration‐resistant prostate cancer.

Methods

We retrospectively analyzed data from 99 consecutive patients (median age 72 years, range 50–88 years) treated with enzalutamide for castration‐resistant prostate cancer between May 2014 and November 2015 after receiving several lines of hormonal therapy.

Results

A total of 45 patients were given ethinylestradiol before enzalutamide. The prostate‐specific antigen response rate (decline in prostate‐specific antigen >50% from baseline) of patients receiving ethinylestradiol and enzalutamide were 51.1% and 41.4%, respectively. Cross‐resistance between ethinylestradiol and enzalutamide was clearly observed in the setting of pre‐docetaxel. In multivariate analysis, the T stage and number of therapies before enzalutamide were the only significant predictors of prostate‐specific antigen response to enzalutamide. However, in patients treated pre‐docetaxel use, prior use of ethinylestradiol was a significant predictor of prostate‐specific antigen response to enzalutamide, whereas ethinylestradiol did not affect the overall survival of these patients.

Conclusions

Cross‐resistance between ethinylestradiol and enzalutamide in the setting of pre‐docetaxel therapy seems to be evident. Therefore, ethinylestradiol should be used prudently before enzalutamide in this setting.     

Cytotoxic chemotherapy in the contemporary management of metastatic castration‐resistant prostate cancer (mCRPC)

For several years, docetaxel was the only treatment shown to improve survival of patients with metastatic castration‐resistant prostate cancer (mCRPC). There are now several novel agents available, although chemotherapy with docetaxel and cabazitaxel continues to play an important role. However, the increasing number of available agents will inevitably affect the timing of chemotherapy and therefore it may be important to offer this approach before declining performance status renders patients ineligible for chemotherapy. Patient selection is also important to optimise treatment benefit. The role of predictive biomarkers has assumed greater importance due to the development of multiple agents and resistance to available agents. In addition, the optimal sequence of treatments remains undefined and requires further study in order to maximize long‐term outcomes. We provide an overview of the clinical data supporting the role of chemotherapy in the treatment of mCRPC and the emerging role in metastatic castration‐sensitive prostate cancer. We review the key issues in the management of patients including selection of patients for chemotherapy, when to start chemotherapy, and how best to sequence treatments to maximise outcomes. In addition, we briefly summarise the promising new chemotherapeutic agents in development in the context of emerging therapies.     

Novel therapeutics for the management of castration-resistant prostate cancer (CRPC)

Androgen-deprivation therapy is the initial treatment for metastatic prostate cancer. Although highly effective, all men who live long enough will eventually experience disease progression and develop castration resistance. Patients who have castration-resistant prostate cancer (CRPC) have a median survival of ≈1-3 years. When evaluating novel therapies for CRPC, one must consider the endpoints measured for determination of response. We will discuss PSA, circulating tumour cells, progression-free survival, overall survival, and other endpoints used in clinical trials. Docetaxel and sipuleucel-T are currently the preferred first-line treatment options for patients with CRPC; cabazitaxel is a new option for patients after docetaxel failure. Patients with CRPC historically have very poor survival, underscoring the unmet need for novel therapeutics. Although many agents appear promising, well-designed randomized phase III trials are necessary to establish their impact on survival and health-related quality of life. Promising new therapies include hormonal agents, such as abiraterone and MDV3100, as well as other novel immunotherapeutics and anti-prostate-specific membrane antigen therapies. In the future, we anticipate therapies tailored to individual patients' malignancies using various molecular analyses.     

Current treatment options for newly diagnosed metastatic hormone-sensitive prostate cancer—a narrative review

Prostate cancer continues to be one of the most commonly diagnosed cancers in men globally and a leading cause of male cancer deaths. The landscape of metastatic hormone-sensitive prostate cancer has significantly changed over the past decade. For many years, androgen deprivation therapy alone through surgical or chemical castration was the mainstay of treatment yielding limited 5-year survival rates. New treatment approaches using Docetaxel chemotherapy or androgen receptor pathway inhibitors to intensify upfront systemic therapy have resulted in significantly improved survival rates compared to androgen deprivation therapy alone. Clinicians are now equipped with an arsenal of drugs capable of prolonging life for metastatic hormone-sensitive prostate cancer patients. Furthermore, new treatment modalities are being tested in clinical trials making treatment of metastatic hormone-sensitive prostate cancer an extremely dynamic space. In this narrative review, we provide an overview of the key systemic treatments for metastatic hormone-sensitive prostate cancer, namely androgen deprivation therapy, novel androgen receptor pathway inhibitors and Docetaxel. We summarise a series of landmark trials that have led to the integration of novel androgen receptor pathway inhibitors and docetaxel into the treatment paradigm for metastatic hormone-sensitive prostate cancer. Lastly, we discuss nursing, financial and side-effect considerations pertaining to the use of these drugs. This article aims to give its readers an understanding of the evidence and clinical aspects of novel therapies in metastatic hormone-sensitive prostate cancer as they become increasingly available for use around the world.     

Clinical development of immunotherapy for prostate cancer

Prostate cancer is the most common cancer in men, and the second leading cause of cancer‐related death in Western countries. Prostate cancer‐related death occurs in patients with metastatic castration‐resistant prostate cancer. Although several new drugs for castration‐resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.     

Adaptation and clonal selection models of castration‐resistant prostate cancer: Current perspective

Prostate cancer is a leading cause of cancer deaths in men worldwide. Management of the disease has remained a great challenge and even more so is the aggressive advanced stage with castration‐resistant behavior. The mechanisms and timing of development of castration‐resistant prostate cancer are unclear and remain debatable. Progression to castration‐resistant prostate cancer is undoubtedly multifactorial, with a number of molecular‐genetic aberrations implicated. However, a key question that remains unanswered is: when in the evolution of prostate cancer do the changes that confer castration resistance occur? Earlier attempts to address this question led to two proposed models: the “adaptation” and the “clonal selection” models. Although the prevailing hypothesis is the adaptation model, there is recent evidence in favor of the clonal selection model. Clarification of the model development of castration‐resistant prostate cancer might significantly alter our diagnostic and therapeutic strategies, and potentially lead to improved outcome of management of this daunting condition. Here we review existing knowledge and current research findings addressing the timing of events in the course of prostate cancer progression to castration‐resistant prostate cancer.     

Docetaxel reintroduction in patients with metastatic castration‐resistant docetaxel‐sensitive prostate cancer: a retrospective multicentre study

OBJECTIVE

To investigate the potential benefit of reintroducing docetaxel chemotherapy in patients with progressive metastatic castration‐resistant prostate cancer (mCRPC) who had initially responded to first‐line docetaxel‐based regimen.

PATIENTS AND METHODS

Records were evaluated retrospectively from French patients with mCRPC who had been included in seven controlled clinical studies of docetaxel as first‐line treatment. We identified patients who were confirmed as responders to first‐line treatment, discontinued for reasons other than disease progression or unacceptable toxicity, and who received further docetaxel chemotherapy for disease progression. The primary objective was to assess efficacy in terms of the prostate‐specific antigen (PSA) response after resuming a docetaxel‐based chemotherapy. Secondary objectives were overall survival and tolerance.

RESULTS

Of the 148 patients who responded to first‐line docetaxel, 50 received further therapy with docetaxel and were analysed. The median (range) response duration to first‐line docetaxel was 10.3 (4.6–45.7) months and the median docetaxel‐free interval was 18.4 (5.0–46.7) months. Docetaxel was reintroduced as second‐line therapy in 52% of patients and as further lines in 48%. After docetaxel reintroduction, 24 patients (48%) had a 50% decrease in PSA level (95% confidence interval, CI, 34.1–61.8%). The median (95% CI) overall survival from docetaxel reintroduction was 16 (13–20) months. Re‐treatment was well tolerated (6% of grade 3–4 haemotoxicity).

CONCLUSION

Docetaxel reintroduction appears to be effective, with favourable tolerance profiles, in patients with mCRPC having responded to first‐line docetaxel, and should be prospectively assessed in clinical trials against alternative therapies or investigational agents given alone or in combination, to define further management.     

Current treatment strategies for advanced prostate cancer

During the past decade, treatment strategies for patients with advanced prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone‐sensitive prostate cancer and recurrent prostate cancer after treatment with curative intent, as well as castration‐resistant prostate cancer, have extensively evolved with the introduction and approval of several new agents including sipuleucel‐T, radium‐223, abiraterone, enzalutamide and cabazitaxel, all of which have shown significant improvement on overall survival. The appropriate use of these agents and the proper sequencing of these agents are still not optimized. The results of several recently reported randomized controlled trials and retrospective studies could assist in developing a treatment strategy for advanced prostate cancer. In addition, prospective studies and molecular characterization of tumors to address these issues are ongoing.     

Current Clinical Trials in Castrate-Resistant Prostate Cancer

Seven years passed since docetaxel/prednisone demonstrated and overall survival benefit, leading to its approval by the FDA for metastatic castration resistant prostate cancer. In 2010, two new treatments, sipuleucel-T and cabazitaxel, were approved by the United States Food and Drug Administration for men with castration-resistant prostate cancer, based upon improvement in overall survival. The progress that has been made in understanding the biological basis of disease progression, particularly the role of the continued activation of the androgen receptor, have led to new treatments that will further improve survival in these patients. Abiraterone, a drug that depletes both intracellular and extracellular sources of testosterone, demonstrated a 3.9-month improvement in survival in patients who failed docetaxel-based chemotherapy. Other drugs targeting the androgen-receptor axis, such as TAK-700 and MDV3100, have demonstrated significant activity in phase 1 and 2 studies, and are currently in phase 3. Agents that target angiogenesis, bone, and novel apoptotic proteins currently are under investigation, either as single agents or in combination with chemotherapy. The challenge for the development of clinical trials will be how these compounds will be sequenced in the future.     

Prostate-specific antigen response to deferred combined androgen blockade therapy using bicalutamide predicts survival after subsequent oestrogen and docetaxel therapies in patients with castration-resistant prostate cancer

Study Type – Prognosis (retrospective cohort analysis) Level of Evidence 2b What's known on the subject? and What does the study add? The additional use of anti‐androgen (deferred combined androgen blockade [CAB] therapy) for patients with castration‐resistant prostate cancer (CRPC) initially treated with androgen deprivation monotherapy (ADMT) can provide a clinical response, although the reported response rates vary widely. Our previous study, which reported a response rate of 66% to deferred CAB therapy, suggested that deferred CAB responders would also respond better to subsequent therapies than non‐responders because the difference in cancer‐specific survival between the deferred CAB responders and the non‐responders was much larger than the progression‐free survival rates for the responders. The present study showed that PSA response to deferred CAB therapy predicts clinical outcomes after subsequent oestrogen and docetaxel therapy. We propose that PSA response to deferred CAB be used for planning individualized treatment that includes secondary hormonal therapy and chemotherapy.

OBJECTIVE

• ? To evaluate whether there is any association between prostate‐specific antigen (PSA) response to deferred combined androgen blockade (CAB) therapy using bicalutamide in patients with castration‐resistant prostate cancer (CRPC), initially treated with castration monotherapy, and the clinical outcomes after subsequent oestrogen and docetaxel therapies.

PATIENTS AND METHODS

• ? Fifty‐six patients with advanced prostate cancer, who were refractory to both initial castration monotherapy and subsequent deferred CAB, received oestrogen therapy (estramustine phosphate 140 or 280 mg/day in 50 patients, diethylstilbestrol diphosphate 100 mg/day orally in six patients). Of the 56 patients, 33 underwent docetaxel therapy (median dose 55 mg/m², every 4–8 weeks, median 6 courses) when they became refractory to oestrogen therapy.
• ? A deferred CAB response was defined as a decrease of >50% in PSA levels after the addition of bicalutamide. The difference in cancer‐specific survival (CSS) after confirmation of resistance to initial castration monotherapy between the deferred CAB responders and the non‐responders was evaluated, and outcomes after oestrogen and docetaxel therapies were also compared between the two groups.

RESULTS

• ? A response to deferred CAB was observed in 27 (48%) of the 56 patients. There was no significant difference between the responders and the non‐responders in pretreatment clinical variables, including Gleason score, metastatic sites, PSA level at diagnosis, and PSA nadir during castration monotherapy.
• ? A deferred CAB response was a significant predictor of CSS after confirmation of resistance to initial castration monotherapy.
• ? The deferred CAB responders had significantly longer progression‐free survival (PFS) (median 3.2 months in the responders, 2.1 month in the non‐responders, P= 0.04) and CSS (median 3.0 years in the responders, 1.5 years in the non‐responders, P= 0.04) after oestrogen therapy. Likewise, PFS (median 8.2 months in the responders, 2.2 months in the non‐responders, P < 0.01) and CSS (median not reached in the responders, 1.4 years in the non‐responders, P < 0.01) after docetaxel therapy was significantly longer in the deferred CAB responders.

CONCLUSION

• ? PSA response to deferred CAB predicts clinical outcomes after subsequent oestrogen and docetaxel therapies in patients with CRPC, and provides useful information for planning individualized optimum treatment courses that include secondary hormonal therapy and chemotherapy.

     

Src as a therapeutic target in men with prostate cancer and bone metastases

While responsive to androgen ablation in its early stages, prostate cancer eventually becomes castration‐resistant and metastasizes preferentially to bone. Once this happens, the disease carries considerable morbidity and is incurable. The process of bone metastasis involves a complex interplay between tumour and bone tissue. The eventual characteristic clinical presentation of disorganized osteoblastic bone lesions is preceded by a facilitatory osteoblastic phase; an osteoblastic component then continues to underlie the process. Increasing evidence has shown a ubiquitous role for Src (a proto‐oncogene tyrosine‐protein kinase) in multiple tumour and bone‐signalling processes involved in prostate tumour progression, driving proliferation, survival, migration and transition to androgen‐independent growth. It is also intimately involved in positively regulating osteoclast physiology. As such, this molecule represents an attractive target for managing progressing prostate cancer. Encouraging results have been obtained in preclinical and clinical studies using Src inhibitors like AZD0530 and dasatinib. Both compounds reduced markers of bone resorption, in patients with cancer and those with advanced castration‐resistant prostate cancer, respectively. Moreover, because Src is central to many mechanisms thought to be responsible for the development of castration resistance, adding Src inhibitors to a treatment regimen might reverse this phenomenon. As a result, many Src inhibitors are in preclinical development. This review explores Src inhibition as a strategy for managing bone metastasis in prostate cancer, with a particular focus on targeting the critical osteoclastic response. Other emerging and novel approaches are also considered.     

Phase II study of docetaxel re‐treatment in docetaxel‐pretreated castration‐resistant prostate cancer

Study Type – Therapy (cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? We show that (i) docetaxel re‐treatment, after a treatment‐free interval, preserves activity; (ii) the treatment is especially well tolerated in patients who were effectively pretreated with docetaxel; and (iii) it could be speculated that combining docetaxel with other agents in this setting might be safe and result in greater activity.

OBJECTIVE

To determine the activity and tolerability of docetaxel re‐treatment after first‐line therapy with docetaxel in castration‐resistant prostate cancer (CRPC).

PATIENTS AND METHODS

Between November 2005 and January 2009, 45 patients initially responding to docetaxel and then experiencing disease progression after a period of biochemical remission of at least 5 months were enrolled in a prospective multicenter study and re‐treated with docetaxel. The primary endpoint was the biochemical response (biochemical partial response defined as >50% prostate‐specific antigen [PSA] decline); secondary endpoints were objective response, toxicity, progression‐free survival (PFS) and overall survival (OS).

RESULTS

Partial PSA responses were observed in 11 patients (24.5%), 4 (25%) of whom also had an objective response. The treatment was well tolerated, with grade 1–2 neutropenia, thrombocytopenia, vomiting and peripheral neuropathy noted in 18 (40%), 11 (24.5%), 8 (17.8%), and 6 (13.3%) patients, respectively. The most common grade 3 toxicity was neutropenia, which was observed in 8 patients (17.8%). Median PFS was 5 months and median OS was 13 months.

CONCLUSIONS

Docetaxel re‐treatment preserves anti‐tumour activity and is well tolerated in a selected population of pretreated patients with CRPC. Further randomized trials are needed to confirm our preliminary results.     

血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现

近年来,去势抵抗性前列腺癌的治疗方法已由传统的抗雄激素及化疗提升到新的雄激素受体信号抑制剂、新一代紫杉醇及免疫疗法阶段。卡巴他赛、恩杂鲁胺、阿比特龙,放射性同位素镭223和sipuleucel-T随机临床试验显示能延长去势抵抗性前列腺癌患者生存期。然而,最终出现肿瘤抵抗也是难免的,去势抵抗性前列腺癌仍是一种主要临床负担,迫切需求新的治疗方法进一步改善CRPC患者生存期及生活质量。新生血管在前列腺癌的形成和进程中发挥至关重要的作用。部分临床试验显示,对失去手术和内分泌治疗时机的去势抵抗性前列腺癌,抗新生血管形成的靶向治疗是一种有效的补充疗法。本文将综述血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现。     

Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy

OBJECTIVES

To characterize changes in secretory clusterin (sCLU) expression in prostate cancer cells after treatment with docetaxel and to determine whether sCLU knockdown can re‐introduce chemosensitivity in a docetaxel‐resistant, androgen‐independent human prostate cancer model.

PATIENTS AND METHODS

A tissue microarray was constructed for 84 radical prostatectomy (RP) specimens from a multicentre Phase II trial of neoadjuvant combined androgen ablation and docetaxel (CUOG‐P01a) and assessed for changes in the expression of the cytoprotective chaperone sCLU. The human prostate cancer cell line PC‐3 was repeatedly exposed to docetaxel chemotherapy in vitro, and a docetaxel‐resistant cell subline (PC‐3dR) was developed and analysed.

RESULTS

sCLU levels were significantly higher in RP specimens treated with neoadjuvant combined androgen ablation and docetaxel than in untreated specimens. Similarly, sCLU expression increased 2.5‐fold in the newly developed docetaxel‐refractory PC‐3dR cell line compared with parental PC‐3 cells. There was a dose‐dependent and sequence‐specific decrease in sCLU levels in PC‐3dR cells using OGX‐011, an antisense oligonucleotide against human sCLU. OGX‐011 and small‐interference RNA both chemosensitized PC‐3dR cells to docetaxel and mitoxantrone in vitro and apoptotic rates in PC‐3dR cells were significantly increased when OGX‐011 was combined with docetaxel. In vivo, growth of PC‐3dR xenografts in nude mice was synergistically inhibited by OGX‐011 combined with paclitaxel or mitoxantrone (by 76% and 44% compared with their mismatch controls, respectively).

CONCLUSION

The present findings indicate that targeted knockdown of sCLU enhances the effects of cytotoxic chemotherapy in docetaxel‐refractory cells, and provide preclinical proof of principle for clinical trials testing OGX‐011 in second‐line chemotherapy regimens for patients with docetaxel‐refractory prostate cancer.