Prostate cancer is one of the most common cancers in the UK for men. It has several different clinical stages used to measure outcomes. A very bad stage is when hormonal therapy is not working well, and cancer has spread to other areas or organs; this can be called the end stage. At this end stage, two key treatment options are Abiraterone and Enzalutamide. Abiraterone has to be given with a medicine called Steroids, while Enzalutamide does not.
Long-term steroid use can increase the risk of developing or worsening conditions like type 2 diabetes and heart disease.
We aim to understand better the impact of treatment on diabetes and heart disease risks. The study initially examined how treatments with Enzalutamide or Abiraterone influence diabetes onset or progression in prostate cancer patients.
In the second part, we will look at three more questions.
We will check if the diabetes and heart disease appear both in GP and hospital records. This will tell us where this information is recorded.
We will look at what other treatments for prostate cancer people have, especially treatments that are usually given with Steroids because using Steroids for a long time might have side effects.
Lastly, we will study how Enzalutamide and Abiraterone might affect the risk of heart disease, as studies from other countries have found that patients who were treated with Abiraterone had a higher risk of having these problems.
Prostate cancer is the second most common cancer worldwide and the fifth most common cause of death. It is the most frequently diagnosed cancer among men in the United Kingdom (UK) with 48,487 new cases reported in 2017, accounting for 26% of all male cancer diagnoses. Prostate cancer encompasses a spectrum of clinical states that a patient progresses through over time.
Metastatic castrate-resistant prostate cancer (mCRPC), is an advanced, incurable form of the disease. Abiraterone acetate (AA) and enzalutamide (Enza) are key treatment options which exert their anticancer effects through different mechanisms of action. AA uses concomitant corticosteroid administration as a prophylactic measure. ENZA does not require concomitant corticosteroids as it acts directly on the androgen receptor without affecting the steroid pathways
Whilst it is well known that long-term corticosteroid use is associated with unwanted side effects including disturbance of glucose metabolism, there has been limited reporting on the risk of T2DM in susceptible patients such as mCRPC.
This study evaluates the risk of Type 2 Diabetes Mellitus (T2DM) in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients in England undergoing treatment with Abiraterone Acetate (AA) versus Enzalutamide (Enza). The amendment includes three additional objectives:
Assessing the number and proportion of mCRPC patients with Type 2 Diabetes and cardiovascular disease at the onset of Enza or AA treatment, using primary care and hospital records. This will address potential underestimation of prevalence when relying solely on hospital data.
Identifying prostate cancer treatments administered before and after Enza and AA. This aims to understand the impact of cumulative corticosteroid exposure, which can increase the risk of severe adverse events like endocrine disorders, infections, and fractures.
Estimating and comparing the risk of cardiovascular events in patients initiating treatment with Enza or AA. Previous studies suggest a higher cardiovascular risk in AA-treated patients.
Composite outcome of incident T2DM diagnosis or worsening T2DM; Duration of treatment on AA or enzalutamide; Incident T2DM diagnosis; Worsening T2DM.
For the extension of the original study:
[1] Prevalence of diabetes type 2 and cardiovascular disease at index date
We will include the following ICD-10 codes: diabetes (ICD-10 codes E10, E11, E12, E13, E14, E88.8); hypertension (ICD-10 code I20); ischaemic heart disease (ICD-10 codes I20, I21, I24, I46, I22, I23, I25), arrhythmia (ICD-10 codes I47, I48, I49), congestive heart disease (ICD-10 codes I42, I50), cerebrovascular disease (ICD-10 codes G45, I60, I61, I62, I63, I64, I65, I66, I67, I69, I69), atherosclerosis and embolic events (ICD-10 codes I70, I71, I72, I73, I74, I77, I79).
[2] Prostate cancer treatments pre- and post-index date
The prostate cancer treatments of interest are androgen deprivation therapy (ADT; goserelin, leuprorelin acetate, triptorelin, buserelin acetate, degarelix), treatments used in combination with ADT but not with corticosteroids ( Enza, sipuleucel-T, radium 223), treatments used in combination with ADT and commonly used with corticosteroids (AA, cabazitaxel, docetaxel, cisplatin, carboplatin), treatments for bone metastases (zoledronic acid, pamidronic acid, alendronic acid, risedronic acid, alendronic acid and colecalciferol, denosumab, raloxifene, teriparatide), first generation non-steroid anti-androgen (bicalutamide, flutamide, nilutamide, cyproterone acetate).
The outcomes of interest are number of patients using each treatment category and treatment duration by treatment category. If patient numbers are sufficiently large, we will consider reporting specific treatments.
[3] Risk of cardiovascular disease
To estimate the incidence of CVD after the index date, the CVD conditions of interest are specified as primary diagnosis admissions, identified by ICD-10 codes in the range I10-I70 and G45, encompassing Hypertension, Heart failure, Ischemic heart disease, Nonrheumatic valve disorders, Atrioventricular block, Arrhythmia, Cerebrovascular disease, Peripheral vascular disease, Pulmonary circulation disorders, Deep vein thrombosis, Cardiac arrest.
For a sensitivity analysis we will include the same cardiovascular conditions but now identified by Read codes, thus providing a more comprehensive data set. The intent of this sensitivity analysis is to assess the robustness of the primary findings by evaluating whether the inclusion of additional clinical information impacts the observed patterns and incidences of CVD.
Robert Snijder - Chief Investigator - Astellas Pharma Europe Ltd. - UK
Robert Snijder - Corresponding Applicant - Astellas Pharma Europe Ltd. - UK
Amy Storfer-Isser - Collaborator - Astellas Pharma US Inc
Christopher Young - Collaborator - Astellas Pharma US Inc
Kirsten Leyland - Collaborator - Astellas Pharma Europe Ltd. - UK
Matthias Stoelzel - Collaborator - Astellas Pharma Europe Ltd. - UK
Nigel Rozario - Collaborator - Astellas Pharma US Inc
Robert Snijder - Collaborator - Astellas Pharma Europe Ltd. - UK
Jerrod Nelms - Collaborator - Astellas Pharma Global Development, Inc. (APGD)
Robert Snijder - Collaborator - Astellas Pharma Europe Ltd. - UK
HES Admitted Patient Care;NCRAS Cancer Registration Data;NCRAS Systemic Anti-Cancer Treatment (SACT) data;ONS Death Registration Data