Triptorelin embonate: a 6-month formulation for prostate cancer

Importance of the field: Luteinizing hormone releasing hormone (LH RH) agonists are the major agent for androgen deprivation therapy in advanced and metastatic prostate cancer. They also have a role in endometriosis, uterine fibroids and central precocious puberty.

Areas covered in the review: Triptorelin embonate 22.5 mg is a new, sustained-release, 6-month formulation of an LH RH agonist. It possesses longer duration of action than the current standard 3-month preparation and appears to have similar efficacy and side effects.

What the reader will gain: The use of LH RH agonists for androgen deprivation in prostate cancer has increased considerably in the last 20 years. Recent work has shown that some of this usage has constituted overtreatment and it is within these newer paradigms of therapy that the new 6-month preparation is situated.

Take home message: The new 6-month LH RH preparation – triptorelin embonate – will be of help in several key areas of therapy for prostate cancer, notably as an adjunct to radiation therapy and chemotherapy. It possesses a similar effect, but with fewer side effects, than those that are now commonly available.     

Management of the side effects of androgen deprivation therapy in men with prostate cancer

Background: Androgen deprivation therapy is the foundation of the medical management of prostate cancer. Androgen deprivation therapy offers improved efficacy when used with local therapy such as external beam radiation therapy and substantial palliation in the metastatic setting. Objective: The adverse events of androgen deprivation therapy include hot flashes, decreased bone mineral density, metabolic changes and gynecomastia. Each of these is described as well as their individual management. Method: The medical literature pertaining to androgen deprivation therapy and its adverse events was reviewed with pertinent publications highlighted. Results: Despite the long history of androgen deprivation therapy use in prostate cancer, ongoing work continues to identify and define the adverse events better. For each complication and particularly with regard to metabolic syndrome, recent efforts continue to characterize the problem and its rational management.     

Abiraterone acetate for castration resistant prostate cancer

Importance of the field: Androgen deprivation therapy has been the standard of care in advanced prostate cancer for >?50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone (termed castration resistant prostate cancer, CRPC). Intratumor and extra-gonadal androgens (specifically adrenal androgens) represent a means for continued androgen receptor-mediated growth in CRPC and have thus become therapeutic targets. One novel therapeutic is abiraterone acetate (AA): an inhibitor of CYP17, an enzyme that catalyzes two key serial reactions in androgen and estrogen biosynthesis. Data from Phase I and II trials suggest that clinically important antitumor activity is seen in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. The toxicity profile has also been found to be acceptable. Two large Phase III clinical trials are currently open to accrual and will hopefully validate the impressive Phase II data.

Areas covered in the review: The chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy and safety/tolerability of AA.

What the reader will gain: Readers will understand the function of non-gonadal androgens, the importance of continued androgen deprivation in advanced prostate cancer and the role/clinical efficacy of AA.

Take home message: The recent realization that non-gonadal sources of androgens (adrenal and intracrine de novo synthesis) may be a major mediator of disease progression forms the biological rationale behind the development of abiraterone acetate and related drugs. Abiraterone acetate is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from Phase I and II trials suggest that prostate specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large Phase III clinical trials are currently open to accrual and, if proven to be efficacious, will result in widespread use of a drug specifically developed to suppress adrenal androgens.     

Zibotentan for the treatment of castrate-resistant prostate cancer

Importance of the field: Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.

Areas covered in this review: This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ET_A receptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ET_A receptor.

What the reader will gain: Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.

Take home message: Modulating the activity of ET-1 through the ET_A receptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ET_A inhibitor, to determine the effect of this agent on overall survival in these patients.     

A comprehensive review of denosumab for bone metastasis in patients with solid tumors

Background:

Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis.

Scope:

Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms ‘denosumab’, ‘RANKL inhibitor’ and ‘bone metastasis’. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab.

Findings:

The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment.

Conclusion:

The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.     

Emerging drugs for prostate cancer

Introduction: Androgen deprivation therapy is the mainstay treatment for patients with prostate cancer who are not candidates for definitive treatment, are diagnosed with advanced disease on initial presentation or progress after primary treatment. Patients who stop responding to androgen deprivation therapy develop castration resistant prostate cancer (CRPC). Emerging drugs undergoing clinical evaluation and drugs that have recently received FDA approval for the treatment of CRPC are reviewed.

Areas covered: As the natural history and signaling pathways of prostate cancer are better understood, new treatments and targeted therapies will be developed. The FDA recently approved 5 medications that increase survival in patients with CRPC. Additional medications and drug classes are being explored that may eventually lead to new treatment options. Articles were identified using a PubMed database search.

Expert opinion: Recent FDA medication approvals and the development of emerging treatments are promising for the future of patients with prostate cancer. The addition of new medications challenges physicians to identify the optimal sequence and/or combination in which newer and older medications should be administered. Physicians treating patients with prostate cancer have a growing responsibility to keep pace with these new medications so that they may counsel and treat patients appropriately.     

Health-related quality of life of exposed versus non-exposed androgen deprivation therapy patients with prostate cancer: a cross-sectional study

Background The survival rate of prostate cancer is relatively higher than other cancers, therefore, the health-related quality of life (HRQoL) becomes a critical issue for the patients. There are limited quality of life data evaluating the difference between androgen deprivation therapy and non-androgen deprivation therapy. Objective To evaluate the HRQoL among prostate cancer patients with androgen deprivation therapy and non-androgen deprivation therapy in an Asian population. Setting The study was conducted at the urology outpatient department in a medical center and a regional hospital in southern Taiwan. Methods We collected the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire-Prostate (QLQ-PR25) among prostate cancer patients with and without androgen deprivation therapy from December 2017 to June 2018. The androgen deprivation therapy subjects in this study were using goserelin, leuprolide, degarelix, bicalutamide, enzalutamide, cyproterone, and abiraterone. The non-androgen deprivation therapy subjects were only receiving radiation therapy or radical prostatectomy. To investigate the determinants of HRQoL between androgen deprivation therapy and non-androgen deprivation therapy, multiple linear regression was used. Main outcomes measures The scores of EORTC QLQ-C30 and QLQ-PR25. Results In total, 182 subjects participated in the study of which 116 (63.74%) were in androgen deprivation therapy user group with a mean age (±?SD, standard deviation) of 75.94 years (±?8.31), and 66 (36.26%) subjects were in non-androgen deprivation therapy user group with a mean age of 70.6 years (±?7.1). androgen deprivation therapy users’ quality of life was significantly lower than non-androgen deprivation therapy users (72.1?±?19.3 vs. 77.8?±?16.6, p?=?0.0493). Conclusions The quality of life of patients with all-stages prostate cancer differs significantly between androgen deprivation therapy users and non-androgen deprivation therapy users. The HRQoL for androgen deprivation therapy users is worse than for the non-androgen deprivation therapy users. Additionally, the symptoms are the key determinants of the quality of life.

     

New therapies for castrate-resistant prostate cancer

Introduction: Prostate cancer is the second leading cause of cancer death in men in the USA, and most of these deaths will occur as a result of castrate-resistant prostate cancer (CRPC) that has progressed despite androgen deprivation therapy. There has been better understanding of castration resistance and molecular mechanisms of prostate cancer progression recently, leading to new treatment strategies.

Areas covered: This review focuses on emerging and new therapies for castrate-resistant prostate cancer, including hormonal therapy, immunotherapy and cytotoxic agents.

Expert opinion: New treatment strategies have been developed in recent years and, with improved understanding of advanced CRPC, additional targeted treatments are expected in the near future. Further cost effectiveness research of these treatments is warranted before dissemination of these promising agents.     

Androgen pathway resistance in prostate cancer and therapeutic implications

Introduction: Metastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance.

Areas covered: This review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer.

Expert opinion: Androgen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available.     

Advancing therapies in metastatic castration-resistant prostate cancer

ABSTRACT

Introduction: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T.

Areas covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies.

Expert opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival.     

Drug design strategies for the treatment of prostate cancer

Introduction: While metastatic prostate cancer remains an incurable tumor, remarkable progress has been made with novel drug design strategies for this incurable disease. Several new agents, including hormonal analogues, cytotoxic chemotherapy drugs, radionuclides and innovative targeted therapies, have recently been approved by the FDA for use in advanced and/or metastatic castrate-resistant prostate cancer. Furthermore, a growing number of new diagnostic or predictive genetic tests have also been incorporated into the management of this disease. Immunotherapy-based approaches have shown promise and have led to drug approvals. Other experimental approaches such as vascular targeting are in early translational clinical trials.

Areas covered: Herein, the authors outline select state-of-the-art approaches in the field. They also discuss the current challenges and future opportunities in the medical care of prostate cancer patients.

Expert opinion: An inherent challenge in the treatment of prostate cancer is to determine which patients need immediate aggressive treatment versus active surveillance. For patients needing aggressive treatment, integrating the sequence of therapeutic interventions, to provide the most benefit, remains a challenge that clinicians face. Recently, several genetic tests have been approved, facilitating early treatment decisions. Innovative targeted therapies are moving towards clinical applications, providing treatment options for tumors previously considered refractory to androgen ablation treatment.     

Neoadjuvant and adjuvant treatment in high-risk prostate cancer

Introduction: High-risk prostate cancer (HRPCa) represents a heterogeneous disease with potential risk for local and distant progression. In these patients, a multi-modal approach consisting of neoadjuvant and/or adjuvant systemic therapies has been proposed. The aim of this review is to summarize the emerging roles of neoadjuvant and adjuvant therapies in HRPCa patients.

Areas covered: This review collects the most relevant phase III randomized controlled trials (RCTs) testing the effect of neoadjuvant and adjuvant systemic therapies in combination with radical prostatectomy (RP) or radiotherapy (RT) for HRPCa patients. Specifically, the review examines the benefit provided by androgen deprivation therapy (ADT), chemotherapy (CHT), and novel antiandrogen agents in this setting. A search of bibliographic databases for peer-reviewed literature was conducted.

Expert commentary: Three decades of RCTs demonstrated that adjuvant ADT is fundamental in HRPCa treated with RT. Conversely, ADT and CHT did not improve the survival of HRPCa patients managed with RP. The recent introduction of novel antiandrogen agents combined with an appropriated selection of patients at risk of cancer progression, may ultimately extend the indication of neoadjuvant and adjuvant therapy in surgical- and radio-treated patients.     

Darolutamide (ODM-201) for the treatment of prostate cancer

Introduction: Androgen deprivation therapy (ADT) is a mainstay initial treatment for advanced hormone-sensitive prostate cancer (HSPC), but disease progression to castration-resistant prostate cancer (CRPC) invariably occurs when patients do not succumb to another disease or comorbidity. Recognition that the androgen receptor (AR) axis continues to drive disease progression has led to the development of several AR-directed approved agents, including abiraterone acetate and enzalutamide. An investigational agent, darolutamide (ODM-201, BAY-1841788), has completed early-phase clinical trials, and two global phase III trials are currently accruing patients.

Areas covered: The unmet clinical need, pharmacokinetics, preclinical development, and clinical efficacy and safety of darolutamide for the treatment of advanced prostate cancer are reviewed. The design of two ongoing phase III trials (ARAMIS and ARASENS) of darolutamide in men with non-metastatic CRPC and metastatic HSPC, respectively, are also discussed.

Expert opinion: Darolutamide is an oral, investigational, high-affinity AR antagonist which has activity against known AR mutants that confer resistance to other second-generation antiandrogens, has minimal blood–brain barrier penetration, and does not significantly increase serum testosterone. These features may offer potential advantages over the second-generation antiandrogens. In the phase I/II ARADES trial, darolutamide demonstrated promising antitumor activity and a favorable safety profile in men with metastatic CRPC.     

The hurdle of antiandrogen drug resistance: drug design strategies

Introduction: Prostate cancer is the second most common cancer death in men after lung cancer, due to distant metastases. While distant prostate cancer is typically castrate resistant, it is not necessarily androgen independent. For this reason, a review of the literature regarding the pathways involved in androgen signaling and therapeutic regimens to treat distant metastases is beneficial to increasing the survival rate of prostate cancer patients.

Areas covered: In this article, the author reviews the literature from the past decade covering metastatic hormone refractory prostate cancer with the aim to examine and identify pathways, therapeutic targets and current therapies for treating castrate-resistant disease. As this area is lacking, the author aims to provide the reader with knowledge of the molecular consequences of castrate resistant prostate cancer, the current treatment paradigms and future directions.

Expert opinion: While there have been advances in the treatment of castrate resistant prostate cancer, only minimal advances have been made in overall survival rate. Due to aberrant mutations and activation in the androgen receptor gene, and the complexity of cell signaling within prostate cancer, the androgen receptor should remain a main target for drug discovery efforts. This author believes that designing compounds that will reduce the activation of the androgen receptor may hold the key to a cure in the future.     

Androgen receptor antagonists: a patent review (2008 – 2011)

Introduction: Androgen receptor (AR) antagonists are predominantly used as chemical castration to treat prostate cancer (i.e., in conjunction with androgen deprivation therapy (ADT)). Unfortunately, castration-resistant prostate cancer (CRPC) typically develops that is refractory to targeted therapy. Insights into CRPC biology have led to the emergence of a promising clinical candidate MDV3100 () and a resurgence in this field. A pipeline of preclinical competitive (C-terminally directed) antagonists was discovered using a variety of innovative screening paradigms. Some inhibit nuclear translocation, selectively downregulate or degrade AR (SARD), antagonize wild-type and escape mutant AR (pan-antagonists) and/or antagonize AR target organs in vivo. Separately, the N-terminal domain has emerged as a promising novel target for noncompetitive antagonists.

Areas covered: AR antagonists whose patents published between 2008 and 2011 are reviewed. Antagonists are organized based on the screening paradigm reported as discussed above.

Expert opinion: Novel mechanisms provide a more informed basis for selecting a competitive antagonist; however, high potency and favorable in vivo properties remain paramount. Noncompetitive antagonists have theoretical advantages suggestive of improved clinical efficacy, but no clinical proof of concept as of yet.     

Systemic therapy for the treatment of endometrial cancer

ABSTRACT

Introduction: Endometrial cancer (EC) is one of the most frequent gynecological cancers worldwide. The gold standard treatment of EC is most certainly surgery and may very well be the only therapy in the early stages of disease. To improve outcomes in non-early EC, adjuvant therapy is often employed but this is not standardized. Adjuvant options can include radiotherapy, chemotherapy or a combination of both. Adjuvant chemotherapy could be indicated in high-risk stage I and II or advanced stage EC. Several clinical trials are ongoing in an attempt to define the optimal adjuvant treatment. Furthermore, chemotherapy is the front-line therapy in advanced unresectable, metastatic or recurrent endometrial cancer.

Areas covered: Herein, the authors review the first-line chemotherapy for the treatment of endometrial cancer and provide their expert perspectives on these therapies.

Expert opinion: Chemotherapy is fundamental in advanced/recurrent EC. Further evidence is needed to characterize the role of adjuvant chemotherapy. Future studies should consider genomic and molecular heterogeneities to identify even more efficient tailored therapies.     

Agonists of luteinizing hormone-releasing hormone in prostate cancer

Introduction: Androgen deprivation therapy (ADT) has been the first-line standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for many decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT.

Areas covered: This article reviews the available data and most recent information concerning the use of LHRH agonists in advanced PCa. This article also reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PCa.

Expert opinion: The introduction and application of agonists of LHRH has modernized and improved the treatment of advanced PCa. The life-saving benefits of LHRH agonists are well established, yet underestimated. Despite their efficacy, agonists of LHRH have several disadvantages or drawbacks including disease flare. The approach to ADT has been recently further refined with the development of the LHRH antagonist degarelix. Degarelix, a highly clinically effective third-generation LHRH antagonist, is currently available in most countries for therapy of advanced PCa. This new drug offers attractive alternatives to LHRH agonists for treatment of advanced PCa. A therapy for castration-resistant PCa based on a targeted cytotoxic analog of LHRH, AEZS-108, is also emerging.     

Contemporary pharmacotherapy for the prevention of skeletal complications in patients with prostate cancer

Introduction: Bones represent the most common metastatic sites in prostate cancer (PCa) patients, and in addition with androgen deprivation therapy, they represent the causative reasons of bone mineral density loss and the onset of skeletal-related events.

Areas covered: An extensive search of PubMed/Medline was performed to identify randomized, Phase II/III controlled trials reporting results regarding the prevention of skeletal morbidity in patients with PCa.

Expert opinion: Preventing bone health is an imperative issue for preserving quality of life and elongate survival and, thus, a concerted effort should be made to monitor skeletal changes and to apply treatment for preventing bone loss. Although several agents have received approval for routine use, it is of paramount importance to identify the appropriate patients who would mostly be benefited by the use of these agents with attention to documenting the toxicity and economic implications. Additionally, it remains to be justified the frequency of administration in order to balance the efficacy and the potential complications.     

Safety of antiandrogen therapy for treating prostate cancer

Introduction: Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy. New-generation antiandrogens have been recently introduced in clinical practice (enzalutamide) or are under evaluation in clinical trials (ARN-509).

Areas covered: This review elucidates the safety profile of antiandrogens, in particular focusing on the tolerability profile of each drug either when employed in combination with castration or as monotherapy, in hormone-naive or in castration-resistant patients.

Expert opinion: Non-steroidal antiandrogens are widely used in the management of hormone-sensitive disease in combination with luteinizing hormone-releasing hormone agonists or in patients failing front-line treatment with androgen-deprivative maneuvers. In selected patients, non-steroidal antiandrogen monotherapy appears to yield comparable results as castration. Novel non-steroidal antiandrogens have been investigated with promising results in castration-resistant prostate cancer. Beyond the safety profile specific to any individual compound, increased testosterone and 17β-estradiol levels are commonly observed during antiandrogen monotherapy, leading to gynecomastia and breast pain. The safety profile of old and novel antiandrogens should be taken into account by clinicians in decision making and in selecting the most suitable patients. Beyond patient selection, full clinical evaluation of patient co-morbidities that might affect the drug tolerability and clinical monitoring are anyway required.