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 prostate cancer: what lies on the horizon?

Androgen deprivation therapy with medical or surgical castration is generally the first-line treatment against advanced prostate cancer. Almost invariably, metastatic prostate cancer overcomes testosterone depletion and grows, despite castrate levels of testosterone. Despite advances in cytotoxic chemotherapy, secondary hormonal therapies are often used after the development of castrate-resistant prostate cancer. Secondary hormonal therapies either lower the androgen levels further or directly antagonize the androgen receptor in prostate cancer cells. We discuss novel secondary hormonal agents that are under development, which work by either inhibiting androgen synthesis or directly targeting the androgen receptor.     

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 receptor splice variant 7 in castration‐resistant prostate cancer: Clinical considerations

Constitutively‐active ligand‐independent splice variants of the androgen receptor are an adaptive response by prostate cancer cells to escape androgen deprivation therapy and novel androgen receptor‐directed treatments. Androgen receptor splice variant 7 is the most common splice variant detected in clinical biospecimens, and emerging data now suggest that the presence of tumoral androgen receptor splice variant 7 might be indicative of primary and acquired resistance to next‐generation androgen pathway inhibitors, such as abiraterone and enzalutamide. At the same time, taxane chemotherapy might retain its efficacy regardless of androgen receptor splice variant 7 status, thus suggesting the potential for a predictive biomarker guiding treatment selection in men with metastatic castration‐resistant prostate cancer. Herein, we review the preclinical data elucidating the structure and function of androgen receptor splice variant 7, we describe the existing clinical data using this biomarker in metastatic castration‐resistant prostate cancer, and we highlight potential therapeutic strategies to target androgen receptor splice variant 7‐expressing prostate cancer.     

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.     

Metabolic changes in patients with prostate cancer during androgen deprivation therapy

Androgen deprivation therapy continues to be widely used for the treatment of prostate cancer despite the appearance of new‐generation androgen‐receptor targeting drugs after 2000. Androgen deprivation therapy can alleviate symptoms in patients with metastatic prostate cancer and might have a survival benefit in some patients, but it causes undesirable changes in lipid, glucose, muscle or bone metabolism. These metabolic changes could lead to new onset or worsening of diseases, such as obesity, metabolic syndrome, diabetes mellitus, cardiovascular disease, sarcopenia or fracture. Several studies examining the influence of androgen deprivation therapy in Japanese patients with prostate cancer also showed that metabolic changes, such as weight gain, dyslipidemia or fat accumulation, can occur as in patients in Western countries. Efforts to decrease these unfavorable changes and events are important. First, overuse of androgen deprivation therapy for localized or elderly prostate cancer patients should be reconsidered. Second, intermittent androgen deprivation therapy might be beneficial for selected patients who suffer from impaired quality of life as a result of continuous androgen deprivation therapy. Third, education and instruction, such as diet or exercise, to decrease metabolic changes before initiating androgen deprivation therapy is important, because metabolic changes are likely to occur in the early androgen deprivation therapy period. Fourth, routine monitoring of weight, laboratory data or bone mineral density during androgen deprivation therapy are required to avoid unfavorable events.     

Androgen deprivation therapy in prostate cancer: are rising concerns leading to falling use?

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Androgen deprivation therapy was originally used for metastatic prostate cancer but is now used to treat all stages of the disease. Once considered to be relatively harmless, androgen deprivation therapy was associated with impaired cognitive function, anemia, loss of muscle strength, osteoporotic fractures, diabetes, and cardiovascular disease by the year 2000. In a large, population‐based sample of prostate cancer patients, the numbers initiating androgen deprivation therapy increased from 1995 to 2001 and then sharply declined to 2005, but the rate of initiation among eligible prevalent cases steadily decreased over that period. Monotherapy with luteinizing hormone‐releasing hormone agonists became the dominant type of androgen deprivation therapy. Changes may be related to fewer cases of late stage disease, potential adverse effects, and new evidence for selected indications and regimens.

OBJECTIVE

? To describe patterns of initiation of androgen deprivation therapy (ADT) in a population‐based cohort of patients with prostate cancer.

PATIENTS AND METHODS

? All patients with prostate cancer in Ontario, Canada, who started ≥90 days of ADT at age ≥66 years in 1995–2005 were classified by ADT regimen: medical castration [oestrogen and/or luteinizing hormone‐releasing hormone (LHRH) agonist); orchidectomy; antiandrogen monotherapy; combined androgen blockade (CAB) medical (medical castration plus antiandrogen); CAB surgical (orchidectomy plus antiandrogen). ? Indications for ADT were as follows: neoadjuvant (short‐term before prostatectomy or radiation therapy); adjuvant (long‐term with prostatectomy or radiation therapy); metastatic disease; biochemical recurrence; primary (localized disease); other. ? We examined trends in ADT regimen and indication over time.

RESULTS

? The number of patients initiating ADT increased from 1995 to 2001 (2106–2916 per year) and declined thereafter to 2200–2300 annually (total n= 26 809). ? However, prostate cancer prevalence doubled over these years, and the rate of ADT initiation decreased from 16 to 7 per 100 person‐years. ? Patterns varied by regimen and indication. Medical castration increased from 12% of all ADT in 1995 to 47% in 2005; orchidectomy decreased from 17 to 4%. Use for metastatic disease remained stable, but adjuvant therapy increased from <3% of all ADT in 1995 to 13% in 2005. Primary therapy was the most common indication, but decreased over time.

CONCLUSIONS

? ADT initiation has fallen and marked changes occurred in treatment patterns for prostate cancer. ? Changes might be driven by increasing awareness of potential harms and costs, and by new evidence supporting ADT for specific indications.     

Gonadotropin‐releasing hormone: An update review of the antagonists versus agonists

Gonadotropin‐releasing hormone agonists and antagonists provide androgen‐deprivation therapy for prostate cancer. Unlike agonists, gonadotropin‐releasing hormone antagonists have a direct mode of action to block pituitary gonadotropin‐releasing hormone receptors. There are two licensed gonadotropin‐releasing hormone antagonists, degarelix and abarelix. Of these, degarelix is the more extensively studied and has been documented to be more effective than the well‐established, first‐line agonist, leuprolide, in terms of substantially faster onset of castration, faster suppression of prostate‐specific antigen, no risk for testosterone surge or clinical flare, and improved prostate‐specific antigen progression‐free survival, suggesting a delay in castration resistance. Other than minor injection‐site reactions, degarelix is generally well tolerated, without systemic allergic reactions and with most adverse events consistent with androgen suppression or the underlying condition. In conclusion, degarelix provides a rational, first‐line androgen‐deprivation therapy suitable for the treatment of prostate cancer, with faster onset of castration than with agonists, and no testosterone surge. Furthermore, data suggest that degarelix improves disease control compared with leuprolide, and might delay the onset of castration‐resistant disease. In view of these clinical benefits and the lack of need for concomitant anti‐androgen treatment, gonadotropin‐releasing hormone antagonists might replace gonadotropin‐releasing hormone agonists as first‐line androgen‐deprivation therapy in the future.     

Androgen deprivation therapy: a primer on concepts and therapeutic options

Prostate cancer is a cause of significant morbidity and mortality in men. Endogenous levels of androgen, produced by the testis and adrenal gland, have a complex and controversial role in the development and progression of prostate cancer. Androgen deprivation therapy (ADT) is a common treatment for prostate cancer, particularly in metastatic tumor cases and in certain cases of locally advanced disease. This paper reviews the surgical and medical options used to produce androgen blockade. Bilateral orchiectomy is the historic gold standard with fewer side effects than medical castration, although currently less frequently utilized. Gonadotropin releasing hormone (GnRH) agonists are the most commonly used medications for achieving castration. Other medications include estrogens, GnRH antagonists, steroidal and non-steroidal anti-androgens and 5-alpha reductase inhibitors. The advantages and side effects of each type of medication are described. Intermittent therapy and continuous androgen deprivation is discussed. While intermittent ADT is currently experimental, there is accumulating evidence demonstrating satisfactory oncologic outcomes with decreased morbidity compared to continuous treatment.     

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.     

The role of docetaxel based therapy for prostate cancer in the era of targeted medicine

Docetaxel based chemotherapy has been shown to modestly extend life, relieve pain and improve the quality of life in patients with metastatic castration‐resistant prostate cancer. Current trials are attempting to build on the backbone of docetaxel by combining it with novel biological agents. Trials are also investigating the role of docetaxel for earlier stages of prostate cancer. No standard second‐line systemic therapy exists and such patients are candidates for clinical trials. The increased understanding of the mechanisms of progressive castration‐resistant prostate cancer is being translated into an increasing pipeline of novel therapies.     

Testosterone in prostate cancer: the Bethesda consensus

What's known on the subject? and What does the study add? Androgen stimulation of prostate cancer (PCa) cells has been the basis for extensive studies evaluating the role of androgen in PCa but the diagnostic measurement of androgen as well as androgen values that potentially influence prognosis are unclear in patients with PCa. The 50 ng/dL threshold has been questioned as a result of reports indicating worse outcomes for levels between 20 and 50 ng/dL. Instead, a 20 ng/dL threshold for serum testosterone after androgren deprivation therapy in patients with advanced PCa was recommended.

OBJECTIVE

• ? Androgen stimulation of prostate cancer (PCa) cells has been extensively studied. The increasing trend of using serum testosterone as an absolute surrogate for castration state means that the diagnostic measurement of testosterone and the values potentially influencing prognosis must be better understood. This is especially important when PCa progresses from an endocrine to an intracrine status.

PATIENTS AND METHODS

• ? We performed a literature review using the MEDLINE database for publications on: (i) hormonal changes with androgen deprivation therapy (ADT); (ii) monitoring hormonal therapy with testosterone measurement; (iii) the efficacy of intermittent androgen deprivation (IAD) compared with continuous androgen deprivation; (iv) the underlying mechanisms of castration‐resistance; and (v) novel treatments for castration‐resistant PCa (CRPCa).

RESULTS

• ? The optimum serum castration levels to be achieved with ADT are still debated. Recently, the 50 ng/dL threshold has been questioned because of reports indicating worse outcomes when levels between 20 and 50 ng/dL were studied. Instead, a 20 ng/dL threshold for serum testosterone after ADT in patients with advanced prostate cancer was recommended.

CONCLUSION

• ? Understanding the mechanisms of androgen biosynthesis relating to PCa as well as prognostic implications might achieve a consensus regarding the role of ADT for both the androgen‐sensitive and ‐insensitive disease state.

     

Advanced Prostate Cancer Consensus Conference (APCCC) 2015 in St. Gallen

In March 2015, the first Advanced Prostate Cancer Consensus Conference (APCC) took place in St. Gallen. 41 experts from 17 countries reviewed important areas of controversy in advanced hormone-naive and castration-resistant prostate cancer and gave therapy recommendations. These results have been recently published in “Annals of Oncology”. While most of the recommendations from St. Gallen are comprehensible, some of them need to be further discussed. Therefore, we as a German expert panel will critically debate the St. Gallen recommendations. For metastatic hormone-naive prostate cancer, continuous androgen deprivation remains the standard. There is no evidence for superiority of primary maximal androgen deprivation. Patients suitable for chemotherapy, especially in the presence of high tumour burden, should receive androgen deprivation plus taxanes upfront. In metastatic castration resistant prostate cancer, novel hormonal agents like abiraterone or enzalutamid should be the treatment of choice in the majority of patients. Taxanes should be used first-line in patients with unfavourable prognostic markers. Radium-223 is an option in symptomatic patients with bone metastases. There is first evidence that second-line hormonal treatment after first-line failure of a novel endocrine agent has a high failure rate. Cabazitaxel should be part of the treatment sequence in patients with a good performance status. Baseline staging for castration-resistant prostate cancer should include CT-abdomen/-chest and bone scan. Radiographic monitoring should be performed 2 to 3 times a year. Determination of PSA and ALP is to take place every 2 to 4 months.     

Considerations for the use of gonadotropin-releasing hormone agonists and antagonists in patients with prostate cancer

Prostate cancer is the second most common cause of cancer-related deaths in men, representing a major source of morbidity and mortality. Androgen deprivation therapy is the primary treatment for patients with advanced prostate cancer at disease presentation, which can be achieved either with surgical or chemical castration. The development of gonadotropin-releasing hormone agonists revolutionized the treatment of advanced prostate cancer, replacing the need for surgical castration. Agonists downregulate gonadotropin-releasing hormone agonist receptors in the pituitary gland, and thus decrease the release of luteinizing hormone and testosterone. Although agonists are a common therapeutic option to date, their use is associated with testosterone surges, metabolic dysfunction and an increase in the risk of cardiovascular disease; they might contribute to tumor flares and potentially an increase in non-cancer mortality. More recently, gonadotropin-releasing hormone antagonists have entered the prostate cancer treatment landscape. Unlike agonists, antagonists directly inhibit the androgen receptor in the pituitary gland, and thus do not cause initial testosterone surges. In this article, we provide a concise review of the mechanism of actions, safety and efficacy of the approved agonists and antagonists for prostate cancer treatment.     

Bicalutamide dosages used in the treatment of prostate cancer

BACKGROUND: Androgen deprivation is often used for the treatment of patients with prostate cancer. Androgen deprivation can be achieved by surgical castration or medical castration, with or without using an antiandrogen. Each of these treatments may be used alone, or an antiandrogen may be used alongside castration to produce combined androgen blockade therapy. METHODS: The nonsteroidal antiandrogen, bicalutamide (Casodex), has been evaluated as a component in combined androgen blockade and as monotherapy. We review the arguments that indicate why a 50-mg once-daily dose of bicalutamide is appropriate in combined androgen blockade, while ongoing clinical trials evaluate 150-mg once-daily as monotherapy in the treatment of prostate cancer. RESULTS: The choice of the 50-mg dose of bicalutamide when used in combined androgen blockade is supported by four main arguments. First, bicalutamide 50 mg is at least equivalent to, if not better than, flutamide 750 mg in terms of receptor affinity, potency, and favorable plasma concentration profile. Second, the reduction in testosterone concentrations produced by medical or surgical castration decreases the potential competition between bicalutamide and testosterone for androgen receptors in prostate cells, allowing the use of a lower dose of antiandrogen in combined androgen blockade than is necessary in monotherapy. Third, bicalutamide 50 mg has an excellent tolerability profile. Fourth, at the 50-mg dose, bicalutamide plus luteinizing hormone-releasing hormone analogue was equivalent to flutamide plus luteinizing hormone-releasing hormone analogue, although there was a trend towards longer survival with bicalutamide. Furthermore, investigations of higher doses of bicalutamide have justified evaluation of bicalutamide 150 mg as monotherapy. First, pharmacodynamic studies reveal an increasing prostate-specific antigen response with increasing dose, which appears to plateau at a dose of around 150-200 mg. Second, in an analysis with 31% mortality, bicalutamide 150 mg appeared to have equivalent efficacy compared with castration in terms of survival in patients with nonmetastatic prostate cancer. CONCLUSIONS: On the basis of available data, bicalutamide 50 mg is an appropriate dose to use in combined androgen blockade, while 150 mg is being evaluated in ongoing clinical trials as a suitable dose for monotherapy.     

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.     

Current concepts in androgen deprivation therapy – is there a “best” endocrine treatment?

Androgen deprivation therapy has become the mainstay treatment for locally advanced and metastatic prostate cancer. Castrate testosterone levels can be achieved by a multitude of treatments. We performed a medline literature search to answer the question, is there a “best” endocrine treatment? In conclusion we found that the “best” endocrine therapy for advanced prostate cancer is complete androgen blockade (CAB) with a luteinizing hormone-releasing hormone (LHRH) agonist and a nonsteroidal antiandrogen.