Clinical trial NCT06902441: Impact of New Hormonotherapy Drugs in Prostatic Cancer on the Risk of Cardiovascular Events : a Pharmacoepidemiology Study Using the French Health Care Claims Database
Official title: Impact of Androgen Receptor Signaling Inhibitors on Cardiovascular Events in Prostate Cancer: a Pharmacoepidemiology Study Using the French Health Care Claims Database
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Prostate Cancer
Keywords: Prostate cancer
Androgen Receptor Signaling Inhibitors
Cardiovascular toxicity
Hormonotherapy
Pharmacoepidemiology
Lead sponsor: University Hospital, Caen
Sponsor class: OTHER
First posted: 2025-03-30
Enrollment: 52000
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with prostatic cancer treated with an ARSI amoung Abiraterone Acetate, Enzalutamide or Apalutamide.

Brief summary: In prostate cancer, whether in advanced or localized cases, hormone therapy is a key treatment. These treatments reduce male hormone levels to slow cancer growth.

More recently, a new class of drugs called Androgen Receptor Signaling Inhibitors (ARSIs) has been introduced. These drugs are used alongside standard hormone therapy and are now given to both advanced and high-risk localized prostate cancer patients.

There are two main types of ARSIs: abiraterone acetate, which blocks androgen production, and enzalutamide, apalutamide, and darolutamide, which prevent cancer cells from using androgens. Doctors choose between these treatments based on patient needs, as no single drug has been proven superior. These therapies have significantly improved patient survival.

However, studies show that 30% of prostate cancer patients die from heart-related problems, a higher rate than in the general population. It is important to understand the link between these treatments and heart risks.

One study found that all ARSIs increase the risk of serious heart issues. However, it did not consider patients' previous heart conditions, which are known to affect heart risk with abiraterone and enzalutamide.

For this reason, we are conducting a study using a large real-world database to compare the heart risks of abiraterone, enzalutamide, and apalutamide while considering patients' existing heart conditions and treatment duration.

Detailed description: In prostate cancer, both in metastatic settings and in many localized cases, androgen suppression via GnRH agonists or antagonists remains the cornerstone of treatment. These androgen deprivation therapies (ADT) aim to reduce circulating androgen levels.

In recent years, Androgen Receptor Signaling Inhibitors (ARSIs) have emerged, prescribed in combination with standard androgen suppression therapy (ADT). These treatments have broad indications in metastatic settings and are now also used in localized high-risk prostate cancer.

A conventional distinction is made between abiraterone acetate, a selective inhibitor of androgen synthesis that blocks CYP 17, and other NGHTs that inhibit the androgen receptor, namely enzalutamide, apalutamide, and darolutamide. The indications for these treatments are often similar, with no clear evidence of superiority of one over another. For instance, in synchronous metastatic castration-sensitive prostate cancer, when treated with NGHTs combined with AST, clinicians may choose between abiraterone acetate, apalutamide, or enzalutamide. Thus, the safety profile of these treatments plays a crucial role in therapeutic decision-making. These new hormonal therapies have significantly improved patient survival.

However, when examining the causes of death among prostate cancer patients, studies have shown that 30% of deaths are due to cardiovascular causes, with an excess risk compared to the general population. It is therefore essential to investigate these cardiovascular events and their associations with administered treatments.

The meta-analysis by El-Taji et al. identified an increased risk of high-grade cardiovascular toxicities for all next-generation hormonal therapies (HR 1.75; 95% CI: 1.50-2.04). This excess risk was observed for each ARSI individually. However, this meta-analysis could not account for patients' cardiovascular history, despite demonstrated associations between pre-existing cardiovascular conditions and the risk of cardiovascular toxicity with abiraterone acetate and enzalutamide.

For these reasons, we have decided to compare cardiovascular toxicities associated with abiraterone, enzalutamide, and apalutamide using a large real-world database, taking into account pre-existing cardiovascular comorbidities as well as treatment exposure duration.

Eligibility criteria: Inclusion Criteria:

* Patients had to begin a treatment with Enzalutamide, Abiraterone or Apalutamide between the 01-01-2018 and the 31-12-2022
* Patients must have a unique ID in the database, to be able to link the data

Exclusion Criteria:

* Previous treatment with another novel androgen receptor signaling inhibitors
* Patients were excluded if they began a chemotherapy treatment in the 6 weeks following the beginning of ARSI

Primary outcomes:
measure: Risk of hospitalization for cardiovascular cause
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023) or outcome
Secondary outcomes:
measure: Risk of hospitalization for hearth failure
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023) or outcome
measure: Risk of hospitalization for atrial fibrillation
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023) or outcome
measure: Risk of hospitalization for ischemic heart disease
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023) or outcome
measure: Risk of hospitalization for hypertensive disease
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023) or outcome
measure: Risk of hospitalization for successfully resuscitated cardiac arrest
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023) or outcome
measure: Risk of death
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023)
measure: Risk of new registration for long term illness
timeFrame: From the beginning of the ARSI to the first date among : death, end of hormonotherapy, study endpoint date (31-12-2023) or outcome
Other outcomes:
Locations:
city: Caen
country: France
facility: CHU Caen
state: Normandie
Study officials:
References:
citation: Baser O, Samayoa G, Dwivedi A, AlSaleh S, Cigdem B, Kizilkaya E. Cardiovascular events among patients with prostate cancer treated with abiraterone and enzalutamide. Acta Oncol. 2024 Apr 9;63:137-146. doi: 10.2340/1651-226X.2024.20337.
citation: Lu-Yao G, Nikita N, Keith SW, Nightingale G, Gandhi K, Hegarty SE, Rebbeck TR, Chapman A, Kantoff PW, Cullen J, Gomella L, Kelly WK. Mortality and Hospitalization Risk Following Oral Androgen Signaling Inhibitors Among Men with Advanced Prostate Cancer by Pre-existing Cardiovascular Comorbidities. Eur Urol. 2020 Feb;77(2):158-166. doi: 10.1016/j.eururo.2019.07.031. Epub 2019 Aug 13.
citation: El-Taji O, Taktak S, Jones C, Brown M, Clarke N, Sachdeva A. Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer: A Systematic Review and Meta-Analysis. JAMA Oncol. 2024 Jul 1;10(7):874-884. doi: 10.1001/jamaoncol.2024.1549.
citation: Ye Y, Zheng Y, Miao Q, Ruan H, Zhang X. Causes of Death Among Prostate Cancer Patients Aged 40 Years and Older in the United States. Front Oncol. 2022 Jul 1;12:914875. doi: 10.3389/fonc.2022.914875. eCollection 2022.
citation: Ploussard G, Baboudjian M, Barret E, Brureau L, Fiard G, Fromont G, Olivier J, Dariane C, Mathieu R, Rozet F, Peyrottes A, Roubaud G, Renard-Penna R, Sargos P, Supiot S, Turpin L, Roupret M; Comite de Cancerologie de l'Association Francaise d'Urologie, Groupe Prostate, Maison de l'Urologie. French AFU Cancer Committee Guidelines - Update 2024-2026: Prostate cancer - Diagnosis and management of localised disease. Fr J Urol. 2024 Nov;34(12):102717. doi: 10.1016/j.fjurol.2024.102717.