Androgen receptor inhibitor treatments: Cardiovascular adverse events and comorbidity considerations in patients with non-metastatic prostate cancer

Apalutamide belongs to the ARTA group. This drug is a new generation selective androgen receptor inhibitor. Patients with prostate cancer develop resistance to castration testosterone levels over timeduring hormone therapy. Therefore, it is necessary to consider additional therapeutic options based on drugs from the ARTA group. Apalutamide is used in the treatment of patients with non-metastatic as well as metastatic prostate cancer. This article presents the most important clinical facts about apalutamide.

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Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial

BMJ Open ◽

10.1136/bmjopen-2020-042953 ◽

2021 ◽

Vol 11 (2) ◽

pp. e042953

Author(s):

Martin John Connor ◽

Taimur Tariq Shah ◽

Katarzyna Smigielska ◽

Emily Day ◽

Johanna Sukumar ◽

...

Keyword(s):

Prostate Cancer ◽

Lymph Node ◽

Androgen Receptor ◽

Randomised Controlled Trial ◽

Phase Ii ◽

Metastatic Prostate Cancer ◽

Controlled Trial ◽

Pelvic Lymph Node ◽

Study Results ◽

Randomised Controlled

IntroductionSurvival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone.MethodsA phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. Primary outcome: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024.Ethics and disseminationApproved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT03763253; ISCRTN58401737

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IL8 Expression Is Associated with Prostate Cancer Aggressiveness and Androgen Receptor Loss in Primary and Metastatic Prostate Cancer

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-19-0595 ◽

2019 ◽

Vol 18 (1) ◽

pp. 153-165 ◽

Cited By ~ 8

Author(s):

Janielle P. Maynard ◽

Onur Ertunc ◽

Ibrahim Kulac ◽

Javier A. Baena-Del Valle ◽

Angelo M. De Marzo ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Metastatic Prostate Cancer ◽

Cancer Aggressiveness

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A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer

Clinical Epigenetics ◽

10.1186/s13148-021-01119-0 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Erik Bovinder Ylitalo ◽

Elin Thysell ◽

Mattias Landfors ◽

Maria Brattsand ◽

Emma Jernberg ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Androgen Receptor ◽

Bone Metastases ◽

Metastatic Prostate Cancer ◽

Tumor Biology ◽

Receptor Activity ◽

Mrna Levels ◽

Androgen Receptor Activity ◽

Patient Prognosis

Abstract Background Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity. Materials and methods Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity. Results Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT. Conclusions A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

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Abstract 16180: Cardiovascular Adverse Events Associated With Androgen Receptor-targeted Therapy Used in the Treatment of Prostate Cancer

Circulation ◽

10.1161/circ.142.suppl_3.16180 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Bishesh Shrestha ◽

Sugam Gouli ◽

Asis Shrestha

Keyword(s):

Prostate Cancer ◽

Heart Failure ◽

Atrial Fibrillation ◽

Adverse Event ◽

Androgen Receptor ◽

Targeted Therapy ◽

Coronary Artery ◽

Adverse Events ◽

Cardiogenic Shock ◽

Cardiovascular Adverse Event

Introduction: Prostate cancer is the second most common cancer in males. Its risk increases with age. So does the risk for cardiovascular disease. Androgen receptor-targeted therapy is now recommended to be added to androgen-deprivation therapy in the treatment of prostate cancer. We present common cardiovascular adverse events seen with the use of anti-androgens medication: abiraterone, enzalutamide, apalutamide, and darolutamide. Methods: We conducted a meta-analysis of 13 multinational randomized phase III clinical trials looking for cardiovascular adverse events in groups that received abiraterone, enzalutamide, apalutamide and darolutamide for treatment of prostate cancer. We analyzed a cohort of 9867 patients in these trials. Results: In the abiraterone usage group (n= 3492), most common cardiovascular adverse event was hypertension reported in 16.03%. Atrial fibrillation was reported in 0.97% and other cardiovascular events (IHD, MI, SVT, VT, and heart failure) were seen in 9.56%. In the enzalutamide usage group (n=4094) hypertension was seen in 10.6%, IHD in 1.88%, and atrial fibrillation was seen in 0.39%. Other unspecified cardiovascular adverse events were reported in 5.98%. In the apalutamide usage group (n=1327) hypertension was seen in 22%. Other cardiovascular adverse events (atrial fibrillation, MI, cardiogenic shock) were seen in 0.96%. In the darolutamide usage group (n=954) hypertension was seen in 6.6%, coronary artery disorders (coronary artery disease, coronary artery occlusion and stenosis) in 3.24%, and heart failure in 1.88%. Conclusions: The most common cardiovascular adverse event with use of anti-androgen medication seen in this large cohort analysis was hypertension with highest incidence seen in apalutamide group. Other cardiovascular side-effects noted were atrial fibrillation, SVT, VT, ischemic heart disease, MI, heart failure, and cardiogenic shock. Abiraterone and enzalutamide are the drugs that have been used in most trials. FDA adverse reaction reporting system (FAERS) shows hypertension as the most commonly reported cardiovascular adverse event with abiraterone and enzalutamide use. More prospective studies are needed to further access cardiovascular risk with use of anti-androgen therapy.

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