Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting

Prostate cancer is the most common noncutaneous cancer and the second leading cause of death from cancer in men in most western countries. Advanced prostate cancer is typically sensitive to androgen‐deprivation therapy, but invariably progresses to the castration‐resistant state. Most current prostate cancer treatments are based on cytotoxicity directed against tumor cells via androgen‐deprivation therapy or chemotherapy. Chemotherapy with docetaxel represents the standard first‐line treatment in patients with castration‐resistant prostate cancer (CRPC). Following progression after treatment with docetaxel, cabazitaxel (XRP6258)–prednisone treatment leads to a significantly longer overall survival (OS) time than with mitoxantrone–prednisone. Several other novel agents are currently being evaluated, including sipuleucel‐T, abiraterone acetate, and MDV3100, as well as the radionuclide alpharadin. The cell‐based immunotherapy sipuleucel‐T produces longer OS times in chemotherapy‐naïve patients, whereas the androgen biosynthesis inhibitor abiraterone acetate results in longer OS times following docetaxel. It is envisioned that these agents will change the standard of care for patients with metastatic CRPC. This review focuses on the clinical development of cabazitaxel and abiraterone acetate.     

Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: Current options and emerging strategies

Prostate cancer is androgen-dependent in its early stages and androgen deprivation therapy represents the most effective first-line therapeutic approach. However, after an initial remission, prostate cancer progresses towards the castration resistant prostate cancer (CRPC) stage, with increased malignancy and resistance to conventional chemotherapy.     

Cabazitaxel: filling one of the gaps in the treatment of prostate cancer

Prostate cancer is the second most frequently diagnosed cancer in men and the fifth most common cancer overall. Globally, more than 900,000 new cases of prostate cancer will be diagnosed in 2010 and more than 260,000 will, unfortunately, die from the disease. In the US, an estimated 217,000 new cases of prostate cancer and 32,000 deaths are expected this year. Definitive therapy (surgery or radiation) is highly effective, but if the tumor escapes the gland, treatment options are limited. For this population of patients, androgen suppression is the cornerstone of initial therapy. Furthermore, progression to castration resistant prostate cancer (CRPC) is inevitable. The current front-line treatment for patients with CRPC is the chemotherapeutic agent docetaxel (administered every 3 weeks). Until now, it is the only agent that has been shown to prolong survival in CRPC. The approval trial for docetaxel found a median overall survival of 19.2 months for patients receiving docetaxel plus prednisone compared to 16.3 months for patients receiving mitoxantrone plus prednisone (p=0.0094). Mitoxantrone plus prednisone is often utilized for its palliative benefits, but two randomized trials failed to demonstrate a survival advantage.     

Novel strategies in the treatment of castration-resistant prostate cancer (Review)

Prostate cancer is the most common cancer in men in Europe and the United States, and the third leading cause of death from cancer in Europe. Survival of prostate cancer cells is dependent on the activation of androgen receptors (AR), that are overexpressed in this tumor. Furthermore, ~90% of prostate cancer patients that respond to first-line androgen deprivation therapy (ADT) undergo rapid progression. This condition is defined as castration-resistant prostate cancer (CRPC). Docetaxel-based regimens significantly improve overall survival (OS) in patients with CRPC and represent the only treatment strategy approved by the Food and Drug Administration (FDA). Recently, abiraterone (second hormonal therapy) and cabazitaxel (new taxane) have been shown to improve survival in patients with CRPC who progressed following docetaxel-based chemotherapy. Vaccine therapy has also been demonstrated to improve OS in patients with asymptomatic or minimally symptomatic metastatic CRPC. Additional therapeutic targets have been analyzed in prostate cancer, including apoptosis, angiogenic receptors, vitamin D and Src pathways. Several phase II studies are ongoing. The high frequency of prostate cancer-related metastatic bone disease has led to consider this pathway as a therapeutic target. To this end, several bone-targeted agents have been investigated, most notably zoledronic acid, which is highly effective at stabilizing the bone and preventing skeletal complications. More recently, a nuclear factor-β ligand (RANKL) inhibitor, denosumab, has been developed for the treatment of bone metastases.     

去势抵抗性前列腺癌化疗耐药机制的研究进展

前列腺癌的发病率和死亡率逐年上升,去势治疗是中晚期前列腺癌的最主要治疗方法,但去势抵抗性前列腺癌为临床治疗难点,化疗虽为后续主要治疗手段,但易出现耐药。最新研究表明,去势抵抗性前列腺癌患者化疗后再使用抗雄激素药物能提高总生存率。本文就近年来去势抵抗性前列腺癌化疗耐药相关机制做一综述,探讨雄激素受体、自噬、JAK/STAT3信号通路在去势抵抗性前列腺癌发生化疗耐药过程中所发挥的调控作用。     

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.     

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.Subject terms: Prostate cancer, Chemotherapy     

Advances in prostate cancer chemotherapy: a new era begins

Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. Over 60 years ago, Huggins and Hodges discovered androgen deprivation as a first-line therapy for metastatic prostate cancer, which leads to remissions typically lasting 2 to 3 years, but in most men prostate cancer ultimately progresses to an androgen-independent state resulting in death due to widespread metastases. Multiple mechanisms of androgen independence have now been documented, including amplification of the androgen receptor as well as signal transduction pathways that bypass the androgen receptor completely. In 2004, two landmark studies demonstrated a survival advantage in androgen-independent prostate cancer patients utilizing docetaxel chemotherapy, setting a new standard of care for this disease. In addition, treatments with the bisphosphonate zoledronic acid and systemic radioisotopes have also been shown to have palliative benefits in this population. Building on these advances, several new traditional chemotherapeutic agents as well as new targeted therapies are under development.     

Systemic therapy and novel agents for metastatic castration resistant prostate cancer

Treatment for metastatic castration resistant prostate cancer (CRPC) represents a critical need. While docetaxel-based chemotherapy has been shown to extend life, relieve pain, and improve the quality of life expanded treatment options are necessary. No standard second line therapy exists and secondary hormonal manipulations before and after docetaxel offer marginal benefits. The increased understanding of the mechanisms of progressive castration resistant prostate cancer has translated into an increasing pipeline of novel therapies such as vaccines, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, anti-angiogenic drugs, small molecule receptor tyrosine kinase inhibitors and more specific targets of the androgen receptor. The future treatment for the most advanced prostate cancer patients is encouraging with broadened clinical benefit.     

The interval from the last cycle of docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer

There is currently no standard treatment after first-line docetaxel-based chemotherapy for patients with castration-refractory prostate cancer (CRPC). Some patients are likely to discontinue first-line docetaxel-based chemotherapy because of either completed treatment or the occurrence of manageable side-effects. The aim of this study was to determine whether a rechallenge with docetaxel might be appropriate in patients with CRPC previously treated with docetaxel.Between December 2004 and July 2009, 39 patients diagnosed with metastatic cancer prostate at the Institut Gustave Roussy were administered subsequent docetaxel after front-line docetaxel-based chemotherapy. The medical records of these patients were extracted from the database. The PSA response rate (PSA decline ?30% and ?50%), progression-free survival (PFS) and overall survival (OS) of patients receiving docetaxel as a subsequent line of therapy were evaluated using consensus criteria. The effect of pre-treatment variables on efficacy was studied.A PSA decline ?30% and ?50% was observed in 64% and 38% of patients, respectively, median PFS was 4.3 months [confidence interval (CI) 95%: 3.6–4.9] and median OS was 15.8 months (CI 95%: 11.7–20.3) in 39 patients who received subsequent docetaxel. The interval between the last cycle of first-line docetaxel and progression [median: 3.0 months; range: 1–30 months] was associated with PFS: median PFS was 3.4 months (CI 95%: 2.6–4.1) and 6.3 months (CI 95%: 3.0–5.6), respectively, in patients with an interval <3.0 months and an interval ?3.0 months, (p = 0.04). Tolerance of re-treatment with docetaxel was acceptable with no toxicity-related death.Re-treatment with subsequent docetaxel in patients with CRPC pretreated with first-line docetaxel is safe and demonstrates some activity. The interval from the last cycle of first-line docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel.     

Changing therapeutic paradigms in castrate-resistant prostate cancer

Prostate cancer is the most common cancer, and the second leading cause of death from cancer, in males in most Western countries. Advanced prostate cancer is initially sensitive to androgen deprivation therapy, but usually progresses to the castration-resistant state. There is now incontrovertible evidence that castration-resistant prostate cancer (CRPC) remains hormone driven, with intratumoral steroid synthesis fueling tumor growth. Several novel agents targeted androgen receptor signaling are currently being evaluated including abiraterone and MDV3100. Recent results of the phase III trial of abiraterone acetate in post-docetaxel patients has shown an overall survival benefit in advanced CRPC. This new treatment is likely to become a new standard of care for patients with metastatic CRPC.     

Current,new and novel therapy for castration-resistant prostate cancer

Androgen deprivation therapy is the standard of care for the initial treatment of metastatic prostate cancer. However, the majority of these patients live long enough to experience disease progression despite castration. This scenario is defined as castration-resistant prostate cancer (CRPC) and has a poor outcome and limited options for treatment. First-line treatment after hormonal therapy failure include secondary hormonal manipulation and docetaxel. Advances in the understanding of the molecular mechanisms underlying CRPC have translated into a recent increase in the number of effective systemic agents, and some of them have been already approved as first and second-line treatment. Despite these advances, the median survival in the first-line setting of metastatic CRPC is approximately 20 months and in the postdocetaxel setting is approximately 15 months. Promising and necessary new therapies in Phase III trials include hormonal agents, new cytotoxics agents, as well as other immunotherapeutics and antiprostate-specific membrane antigen therapies.     

The European Medicines Agency Review of Abiraterone for the Treatment of Metastatic Castration‐Resistant Prostate Cancer in Adult Men After Docetaxel Chemotherapy and in Chemotherapy‐Naïve Disease: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration‐resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel‐based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel‐based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54–0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy‐naïve patient population, median radiographic progression‐free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45–0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema.     

A case of castration-refractory prostate cancer showing marked decrease of serum PSA level after zoledronic acid treatment with estramustine phosphate and prednisolone

A 66-year-old man was referred to our outpatient clinic for an elevated serum prostatic-specific antigen (PSA 4,319 ng/ mL). Magnetic resonance imaging (MRI) showed multiple metastatic lesions in the bones. The patient had received androgen deprivation therapy, but six months after treatment, he was diagnosed as having prostate cancer refractory to hormones. Combined treatment with docetaxel (DOC 30 mg/m2/week )and estramustine phosphate (EMP 560 mg/day) was initiated as first-line chemotherapy, but the treatment was discontinued because of side effects. Then, treatment with zoledronic acid was started(4 mg/4 weeks)and the PSA level decreased dramatically from 457.2 ng/mL to 5.5 ng/mL. Seven months after the diagnosis of CRPC, MRI showed a decrease ofbone metastases, and the PSA levels continued to decrease, eventually reaching 0.3 ng/mL. Zoledronic acid appears to not only show efficacy in preventing skeletal-related events, but has a potential antitumor effect in patients with metastatic CRPC.     

去势抵抗性前列腺癌的药物治疗现状

雄激素剥夺疗法(ADT)一直是晚期前列腺癌的代表性疗法。当前列腺癌进展为去势抵抗性前列腺癌(CRPC)时,ADT的抗性也随之出现。目前,多西他赛是首个被美国食品药品监督管理局(FDA)批准用于CRPC的细胞毒性化疗药物。另外,还有阿比特龙、恩杂鲁胺等药物也获得FDA批准,且这些药物都显示出良好的生存获益。本文对这些疗法的临床试验和生存获益进行了回顾,并对这一领域的新兴药物进行了讨论。本综述将对CRPC的药物治疗现状进行陈述,并为临床用药提供参考。     

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.     

Castration-resistant metastatic prostate cancer: current status and treatment possibilities

Prostate cancer (PCa) is the most common cancer in the male population in Western countries, second to skin cancer. Hormonal therapy allows long-lasting and effective control of cancer-related symptoms in advanced stages; however, in almost all patients with metastatic PCa the disease will progress when it becomes castration-resistant (CRPC). Chemotherapy with docetaxel was a turning point in CRPC, as, for the first time, it resulted in an increased survival time in comparison with mitoxantrone and prednisone. Combination therapy with docetaxel and prednisone is the first-line treatment of choice. Once the cancer has progressed, there is no clear alternative, although some new agents have shown promise in the treatment of this type of cancer. This review will provide an overview of the current status of CRPC, including clinical status, prognosis, firstline treatment and new second-line treatment options.     

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.     

Development of abiraterone acetate,a 17-alpha hydroxylase C17,20-lyase inhibitor as a secondary hormonal therapy in prostate cancer

Although androgen deprivation therapy is widely accepted as the standard approach to patients with advanced prostate cancer, most patients eventually develop progressive disease despite castrate levels of testosterone. Despite its name, castration resistant prostate cancer (CRPC) is nonetheless dependent on continued activation of the androgen receptor via various signaling pathways. New secondary hormonal therapies seek to prolong suppression of the AR and thus delay the development of truly hormone “refractory” prostate cancer. Adrenal androgen synthesis represents one potential mechanism of continued AR-mediated growth in CRPC, and thus a potential target for therapy. Abiraterone acetate is an orally available small molecule that specifically inhibits the 17-alpha hydroxylase and C17,20-lyase enzymes within the adrenal steroid synthetic pathway. Preliminary data from phase I dose escalation trials suggest that PSA declines occur in a large proportion of patients and that the toxicity profile is acceptable. If ultimately proven to be efficacious in phase II/III trials, abiraterone acetate would represent the first agent mechanistically developed for the purpose of adrenal androgen suppression in prostate cancer.