Current and emerging treatment modalities for metastatic castration-resistant prostate cancer

Docetaxel-based therapy is established as the standard first-line chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), based on results from two landmark Phase III studies. However, prognosis remains poor, with a median survival of less than 2 years. There is no standard of care for patients who progress during or after docetaxel treatment, which represents a real unmet medical need. Several small retrospective studies suggest that patients with mCRPC who responded to first-line docetaxel-based therapy are sensitive to re-treatment, but a survival benefit in prospective randomized trials has not been demonstrated. Epithelial-stromal interactions in the tumour microenvironment appear to play a central role in prostate cancer progression and response to therapy. Recent insights into the molecular mechanisms that underpin prostate cancer progression have allowed the identification of potential therapeutic targets. New agents, including angiogenesis inhibitors, hormone therapies, chemotherapies, bone targeting agents, vaccines and immunotherapies are currently undergoing clinical development in advanced prostate cancer using docetaxel as a backbone. Several Phase III studies have now been completed. Sipuleucel-T prolonged survival compared with placebo in asymptomatic or minimally symptomatic patients with mCRPC. Cabazitaxel plus prednisone prolonged survival in patients with mCRPC who progressed during or after docetaxel-based therapy compared with the active agent mitoxantrone, plus prednisone. Multidisciplinary management and optimization of the role and timing of new agents in this evolving treatment continuum will be critical to maximizing patient outcomes. Identification of predictive markers and better gene expression profiling will be critical to tailoring therapies to individual patients and disease states, whereas validated surrogate markers of overall survival will help accelerate drug approval.     

Patient Selection for Therapy in Prostate Cancer

The two major challenges in prostate cancer today are biochemical failure and hormone-refractory disease. Biochemical failure, manifested by a rising prostate-specific antigen (PSA) level following failure of local therapy, is the most common presentation of advanced prostate cancer. Hormonal therapy can produce dramatic but short-lived response rates in metastatic hormone-sensitive prostate cancer, while chemotherapy possesses the ability to induce significant response rates in refractory disease. Clinicians agree that patients with symptomatic advanced prostate cancer should receive immediate androgen ablation therapy; however, there is debate regarding treatment for asymptomatic patients with advanced disease. While there is no clear evidence to support the widespread use of aggressive interventions such as hormonal therapy with or without chemotherapy in men with biochemical failure, there are a number of studies indicating that early hormonal therapy may prolong the time to disease progression and survival for some patients, with this benefit being more pronounced in men with less tumor burden. Numerous questions remain for patients with advanced prostate cancer regarding optimal therapy, and until these questions are answered, the use of early hormonal therapy with or without chemotherapy for the management of locally advanced and metastatic disease is warranted.     

Difficult clinical cases in prostate cancer: multidisciplinary staff, the rational principles of adjuvant therapy and other therapeutic options

Difficult clinical cases of locally advanced prostate cancer at high-risk of progression should be discussed during a collegial decision-making process with different clinical specialists (surgeon, radiotherapist, oncologist, chemotherapist). Scientific consensus exists to give an adjuvant therapy after initial curative local treatment in patients with unfavourable prognostic features. For patients with locally advanced prostate cancer extending beyond the capsule (pT3) or with positive surgical margins, studies have shown that immediate postoperative radiotherapy is to eradicate the microscopic disease left in the surgical bed. Studies have shown the potential benefit of cytotoxic chemotherapy in terms of overall survival and median time to progression in patients with metastatic hormone-refractory prostate cancer. Active clinical research is underway to study neoadjuvant systemic chemotherapy before radical prostatectomy. There are also currently several clinical trials that are investigating the addition of chemotherapy in patients at high-risk of progression in the postprostatectomy setting. Antiandrogen therapy after radical prostatectomy has been shown in randomised studies to significantly reduce the risk of objective clinical progression in patients with high-risk localized prostate cancer. Immediate hormonal therapy with bicalutamide is a valuable therapeutic option in men having prostate cancer with such clinicopathological features.     

Therapeutic options for hormone-refractory prostate cancer in 2007

Prostate cancer is the most commonly diagnosed cancer in American men and a major health problem. While localized disease has an excellent chance for cure, metastatic disease leads to androgen-independent progression and death within a few years. Although docetaxel represents an important therapeutic milestone and is the current standard of care for metastatic hormone-refractory prostate cancer (HRPC), most patients eventually progress because of clonal selection of therapy-resistant cells or the development of cells with a drug-resistant phenotype. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy, the rational design of targeted therapeutics is possible. Over the last few years, many gene targets that regulate apoptosis, proliferation, and cell signalling have been identified, and numerous novel compounds have entered clinical trials either as single agents or in combination with cytotoxic chemotherapy. Neoadjuvant trials in particular must be further encouraged since they allow detection of biological activity in the prostatectomy specimen. This article reviews new treatment options available for men with advanced prostate cancer. Even though HRPC remains incurable, it is not untreatable. Recent findings are very promising, but challenges remain in demonstrating effective anti-tumor activity and showing a clinically relevant survival benefit in Phase III trials.     

Update: Immunological Strategies for Prostate Cancer

Prostate cancer is the second most common cause of cancer-related death in US men. Along with initial therapy using surgery, radiotherapy, or cryotherapy, hormonal therapy is the mainstay of treatment. For men with advanced (metastatic) disease, docetaxel-based chemotherapy is US Food and Drug Administration (FDA)-approved, and provides a significant survival advantage. This relative paucity of treatment options drives an ongoing quest for additional treatment modalities; among these is immunotherapy. The concept that prostate cancer is a malignancy that can be targeted by the immune system may seem counterintuitive; certainly kidney cancer and melanoma are more traditionally thought of as immune responsive cancers. However, prostate cancer arises in a relatively unique organ and may express a number of proteins (antigens) against which an immune response can be generated. More importantly, several of these agents have now demonstrated a significant survival benefit in randomized controlled clinical trials, and one agent in particular (Sipuleucel-T, Dendreon Corporation, Seattle, WA) could be FDA-approved in 2010. This update summarizes recent clinical developments in the field of prostate cancer immunotherapy, with a focus on dendritic cell vaccines, virus-based vaccines, DNA-based vaccines, and cell-based vaccines. In addition, the notion of agents that target immune checkpoints is introduced. Enthusiasm for prostate cancer immunotherapy is founded upon its potential to mediate targeted, specific, tumor cell destruction without significant systemic toxicity; however, this has yet to be fully realized in the clinical arena.     

Mechanisms of resistance in castration-resistant prostate cancer (CRPC)

Despite advances in prostate cancer diagnosis and management, morbidity from prostate cancer remains high. Approximately 20% of men present with advanced or metastatic disease, while 29,000 men continue to die of prostate cancer each year. Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced or metastatic prostate cancer since Huggins and Hodges first introduced the concept of androgen-dependence in 1972, but progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. CRPC, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. These mechanisms include AR amplification and hypersensitivity, AR mutations leading to promiscuity, mutations in coactivators/corepressors, androgen-independent AR activation, and intratumoral and alternative androgen production. More recently, identification of AR variants (ARVs) has been established as another mechanism of progression to CRPC. Docetaxel chemotherapy has historically been the first-line treatment for CRPC, but in recent years, newer agents have been introduced that target some of these mechanisms of resistance, thereby providing additional survival benefit. These include AR signaling inhibitors such as enzalutamide (Xtandi, ENZA, MDV-3100) and CYP17A1 inhibitors such as abiraterone acetate (Zytiga). Ultimately, these agents will also fail to suppress CRPC. While some of the mechanisms by which these agents fail are unique, many share similarities to the mechanisms contributing to CRPC progression. Understanding these mechanisms of resistance to ADT and currently approved CRPC treatments will help guide future research into targeted therapies.     

Stratégies thérapeutiques actuelles du cancer de la prostate hormonorésistant

Prostate cancer is the most common cancer diagnosed in American males, and is the second leading cause of cancer-related deaths. Most patients who develop metastatic disease will initially respond to androgen deprivation, but response is invariably temporary. Most patients will develop androgen-independent (“hormone-refractory”) disease that results in progressive clinical deterioration and ultimately death. This progression to androgen independence is accompanied by increasingly evident DNA instability and alterations in genes and gene expression, including mutations in p53, over-expression of Bcl2, and mutations in the androgen receptor gene, among others. Treatment options for hormone-refractory disease include intensive supportive care, radiotherapy, bisphosphonates, second-line hormonal manipulations, cytotoxic chemotherapy and investigational agents. A post-treatment reduction in the level of prostate specific antigen (PSA) by 50% has been shown to correlate with survival and has been accepted by consensus as a valid endpoint in clinical trials. Chemotherapeutic agents such as mitoxantrone, estramustine, and the taxanes have yielded improved response rates and palliative benefit, but not improved survival. Therefore, current efforts must be focused on enrolling patients onto clinical trials of investigational agents with novel mechanisms of action, and on using survival, time to progression, and quality of life as end points in routine clinical practice.     

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.     

Secondary hormonal therapy for advanced prostate cancer

PURPOSE: Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer. MATERIALS AND METHODS: A comprehensive review of the peer reviewed literature was performed on the topic of secondary hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds, gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer. RESULTS: Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate Cancer Endpoints Workshop were reviewed in the context of developing new agents. CONCLUSIONS: Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indications and their potential side effects.     

New drugs in prostate cancer

PURPOSE OF REVIEW: The survival of hormone-refractory metastatic prostate cancer patients has improved with the use of docetaxel-based chemotherapy. The survival benefits, however, are modest suggesting that rationally designed therapeutic approaches are needed. We discuss recent developments in the therapeutic approach to advanced metastatic hormone-refractory prostate cancer, including molecularly targeted therapy, signal transduction inhibitors, stem-cell targeted therapy, anti-angiogenic compounds, vaccines and immunomodulating agents, differentiation agents, cytotoxics, and pro-apoptotic agents. RECENT FINDINGS: Over 200 compounds have entered clinical development for use in advanced prostate cancer, alone or in combination with cytotoxic agents such as docetaxel, or in other combinations. This article will review the results of emerging targets since the approval of docetaxel in 2004, concentrating on some of those compounds that, in our opinion, have the greatest potential and rationale for use. SUMMARY: The growing field of targeted molecular therapy of prostate cancer has opened up numerous opportunities for therapeutic impact. Knowledge of the molecular determinants of progression, relapse after local therapy, chemotherapeutic resistance, and hormone refractoriness remains essential in the rational design of clinical trials of these agents. Given the complexity, heterogeneity, and crosstalk of molecular pathways and the molecular lesions in prostate cancer, combination or sequential therapy may be a necessary step towards significant therapeutic progress. Novel translational clinical trial methodologies may assist in a more rapid identification of active compounds at biologically active doses for phase-III testing.     

Targeting the androgen receptor signalling axis in castration‐resistant prostate cancer (CRPC)

What's known on the subject? and What does the study add? Castration resistance has been appreciated for decades, and several mechanisms theorising on this effect have been proposed. A rich pipeline of novel agents, including abiraterone and MDV3100, have provided proof of principle that novel agents targeting the AR signalling pathway with superior selectivity and activity than predecessors have yielded significant clinical benefit for patients with metastatic castration‐resistant prostate cancer. Our review provides an update in the development of several novel agents targeting the AR signalling pathway now in clinical testing, as well as review novel therapies in development with distinct mechanisms of action showing promising preclinical activity.

• ? Despite undergoing local therapy with curative intent, 20–30% of patients with prostate cancer will ultimately development metastatic disease, leading to morbidity and mortality.
• ? Androgen‐deprivation therapy (ADT) for men with metastatic prostate cancer results in transient clinical benefit, but ultimately, cancers progress despite castrate levels of serum testosterone, a clinical state classically referred to as ‘hormone refractory’ disease.
• ? In this review, we examine mechanisms of resistance to ADT that have redefined our understanding of the more appropriately termed ‘castration resistant’ disease, and have paved the way for a new generation of therapeutics targeting the androgen signalling axis in advanced prostate cancer.

     

Androgen deprivation therapy for prostate cancer: current status and future prospects

Androgens play a major role in promoting the development and progression of prostate cancer. As a result, androgen ablation or blockade of androgen action through the androgen receptor (AR) has been the cornerstone of treatment of advanced prostate cancer. Different strategies involving this hormonal therapy produce a significant clinical response in most of the patients, but most responders eventually lose dependency, resulting in mortality. Thus, whether hormonal therapy contributes to the improvement of overall survival rates, especially in patients with advanced prostate cancer, remains controversial. However, patients with advanced disease clearly have a benefit from androgen deprivation-based treatment for palliating their symptoms and for improving the quality of their lives. In order to improve overall survival, novel treatment strategies that prolong the androgen-dependent state and that are useful for androgen-independent disease based on specific molecular mechanisms need to be identified.     

Combining immunotherapies for the treatment of prostate cancer

Sipuleucel-T, a therapeutic dendritic-cell vaccine, was Food and Drug Administration–approved for prostate cancer in 2010. No new immunotherapies for prostate cancer have been approved since. However, novel agents and combination approaches offer great promise for improving outcomes for prostate cancer patients. Here we review the latest developments in immunotherapy for prostate cancer. Sipuleucel-T has demonstrated a survival advantage of 4.1 months in metastatic castration-resistant prostate cancer. PSA-TRICOM (PROSTVAC), a prostate-specific antigen–targeted vaccine platform, showed evidence of clinical and immunologic efficacy in early-phase clinical trials, and results from a phase III trial in advanced disease are pending. While immune checkpoint inhibitors appear to have modest activity as monotherapy, preclinical and clinical data suggest that they may synergize with vaccines, poly [ADP-ribose] polymerase inhibitors, and other agents. Several clinical studies that combine these therapies are underway.Combining prostate cancer vaccines with immune checkpoint inhibitors has great potential for improving clinical outcomes in prostate cancer. Such combination approaches may create and then recruit tumor-specific T cells to tumor while also increasing their effector function. Other emerging agents may also enhance immune-mediated tumor destruction.     

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.     

The changing pattern of management for hormone-refractory, metastatic prostate cancer

Prostate cancer responds initially to hormonal manipulation by androgen withdrawal and peripheral androgen blockade. The inevitable progression to a hormone-refractory state is accompanied by an exacerbation of local symptoms and metastatic spread, principally to the bones, which has a considerable impact on quality of life and survival. Treatment of hormone-refractory prostate cancer is palliative, and surgery and radiotherapy are used for the relief of lower urinary tract symptoms and localized painful bony metastases. Systemic treatments are not widely accepted in this setting, but clinical trials have demonstrated the potential for bone targeting agents such as strontium-89 and the bisphosphonates to palliate painful bone metastases and to delay progression in certain settings. Chemotherapy with mitozantrone in combination with steroids has previously been shown to have palliative benefits and to delay progression. The additional costs incurred by the use of chemotherapy or bone-targeting therapies may be offset by gains in overall care with fewer in-patient admissions compared with steroid monotherapy. Recent clinical trials have demonstrated that docetaxel significantly improves patient quality of life, and importantly, increases survival. Future studies investigating the timing of chemotherapy, combinations with existing treatments or other novel therapies are underway.     

Immunotherapy for metastatic prostate cancer

Chemotherapy with docetaxel is the standard treatment for men with metastatic prostate cancer, and results in statistically significant improvements in survival, as well as in quality of life. However, the response rate to single-agent docetaxel is approximately 40% to 45%, emphasizing a need for alternative approaches. More significantly, with the onset of early, PSA-based detection of prostate cancer and closer follow-up, many men present with metastatic disease that remains asymptomatic. For such patients, the side effects of chemotherapy would compromise their current performance status and, thus, a nontoxic, early treatment option that could improve overall survival would be highly desirable. Immunotherapy represents one such approach; a number of clinical trials have suggested a survival benefit for immunotherapy in metastatic prostate cancer and confirmed that these agents are generally well-tolerated. As is the case for chemotherapy, it is doubtful that maximal survival benefit will be achieved with single-agent immunotherapy; experimental treatments in which mechanistically distinct immunotherapy approaches are combined, as well as approaches in which immunotherapy is combined with chemotherapy or hormonal therapy are currently under investigation. This review will discuss the mechanisms of action of several immunotherapy approaches for metastatic prostate cancer, focusing on active immunotherapy as opposed to administration of anti-tumor antibodies. The relative advantages and disadvantages of current approaches will be noted, and ongoing clinical trials will be highlighted.     

Current Topics in the Treatment of Hormone-Refractory Prostate Cancer

Following endocrine therapy, progression to a hormone-refractory state is inevitable in patients with locally advanced or metastatic prostate cancer, if they survive competing mortality. Current treatment options are essentially palliative, with the aim of maintaining quality of life and prolonging survival.Following the failure of primary androgen ablation, a number of treatment strategies are available. Exploitation of the anti-androgen withdrawal syndrome and further hormonal therapies are well-established treatments. More recently, interest in chemotherapy has been renewed owing to demonstrable benefits in prostate specific antigen (PSA) response and pain palliation, albeit without any improvements in survival.However, future treatment options that can prolong survival and maintain quality of life for patients with hormone-refractory prostate cancer (HRPC) are constantly being sought. An increased understanding of the molecular biology of prostate cancer has led to the identification of novel targets and agents. The evaluation of these, and possible addition of them to our armamentarium against prostate cancer, is the goal of ongoing clinical trials.     

Avances en uro-oncología «OncoForum»: lo mejor del 2019

ObjectiveReview the latest evidence on urologic oncology on kidney, bladder and prostate tumors.MethodsAbstracts on kidney, bladder and prostate cancer presented at the 2019 congresses (EAU, AUA, ASCO and ESMO) and the publications with the greatest impact in this period, with the highest evaluation by the OncoForum committee, are reviewed.ResultsIn patients with metastatic kidney cancer, regimens including immunotherapy (nivolumab + ipilimumab, pembrolizumab) have been shown to be superior to sunitinib in terms of survival. In patients with non-muscle invasive bladder cancer, pembrolizumab has been shown to be an effective alternative in those refractory to bacillus Calmette-Guérin, while in patients with metastatic urothelial cancer, third-line enfortumab vedotin achieved a significant response rate (44%). In patients with localized prostate cancer (PCa), ultrafractionated external radiotherapy did not show any greater acute toxicity than fractionated or hypofractionated radiotherapy. The benefit of enzalutamide and apalutamide associated with castration has been confirmed in M1 PCa patients, regardless of disease volume. In patients with castration-resistant M0 PCa, treatment with enzalutamide, apalutamide or darolutamide has been associated with a delay in the occurrence of metastasis and prolonged survival. Cabazitaxel has demonstrated a survival benefit in patients with metastatic CRPC, while olaparib showed anti-tumor activity after chemotherapy in those tumors with mutations in DNA repair genes.ConclusionsThese data show the implementation of immunotherapy as a novel alternative against renal and bladder cancer. The arrival of new agents for advanced urothelial carcinoma should be highlighted, and the efficacy of enzalutamide and apalutamide in de novo metastatic prostate cancer is established. In metastatic CRPC, cabazitaxel and olaparib (targeting mutations) are promising therapeutic options.     

Neoadjuvant Treatment of High-Risk,Clinically Localized Prostate Cancer Prior to Radical Prostatectomy

Multimodal strategies combining local and systemic therapy offer the greatest chance of cure for many with men with high-risk prostate cancer who may harbor occult metastatic disease. However, no systemic therapy combined with radical prostatectomy has proven beneficial. This was in part due to a lack of effective systemic agents; however, there have been several advancements in the metastatic and castrate-resistant prostate cancer that might prove beneficial if given earlier in the natural history of the disease. For example, novel hormonal agents have recently been approved for castration-resistant prostate cancer with some early phase II neoadjuvant showing promise. Additionally, combination therapy with docetaxel-based chemohormonal has demonstrated a profound survival benefit in metastatic hormone-naïve patients and might have a role in eliminating pre-existing ADT-resistant tumor cells in the neoadjuvant setting. The Cancer and Leukemia Group B (CALGB)/Alliance 90203 trial has finished accrual and should answer the question as to whether neoadjuvant docetaxel-based chemohormonal therapy provides an advantage over prostatectomy alone. There are also several promising targeted agents and immunotherapies under investigation in phase I/II trials with the potential to provide benefit in the neoadjuvant setting.     

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.