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Jury still out on cardiovascular safety of prostate cancer treatments

PRONOUNCE trial presented in a Hot Line Session today at ESC Congress 2021

Pharmacology and Pharmacotherapy
Cardiotoxicity of Drugs

Sophia Antipolis, France – 30 Aug 2021:  The relative cardiovascular safety of different types of androgen deprivation therapy (ADT) for prostate cancer remains unresolved after the PRONOUNCE trial was terminated early. The late breaking research is presented in a Hot Line session today at ESC Congress 2021.1

More than one million men are diagnosed with prostate cancer worldwide every year.2 These patients are at high risk of developing cardiovascular disease and are more likely to die from cardiovascular disease than their healthy peers.3,4

Approximately 50% of all patients with prostate cancer will be prescribed ADT at some point in their illness. ADT has been associated with heart disease and stroke, particularly in men with pre-existing cardiovascular disease.5 However, it is unclear whether this is driven by the method of androgen deprivation – i.e. orchiectomy, testosterone antagonists, or modulation of the gonadotropin-releasing hormone (GnRH) receptor. Previous research has suggested that GnRH antagonists may be associated with a preferable cardiovascular safety profile.

PRONOUNCE was the first randomised clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist versus GnRH agonist in patients with prostate cancer. This was also the first interdisciplinary, multinational cardio-oncology outcomes-based trial that has involved close collaboration between urologists, oncologists and cardiologists.

The trial was initially designed to enrol 900 men with prostate cancer and concomitant atherosclerotic cardiovascular disease. Participants were randomised 1:1 to the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first occurrence of a major adverse cardiovascular event (MACE), defined as a composite of death, myocardial infarction or stroke through 12 months.

Enrolment was slower than anticipated and the trial was terminated prematurely with fewer than half of the planned 66 endpoint events in 545 randomised patients.

The analysis included 545 men with an average age of 73.2 years. At 12 months, no statistically significant difference in the rate of MACE was observed between patients treated with degarelix compared with those treated with leuprolide. There were 15 (5.5%) and 11 (4.1%) primary endpoint events in the degarelix and leuprolide groups, respectively (p=0.53).

Principal investigator Professor Renato Lopes of Duke University Medical Center, Durham, US said: “PRONOUNCE is the first, international, randomised clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to smaller than planned numbers of participants and events and no difference in MACE at one year between patients assigned to degarelix or leuprolide was observed. Thus, the relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. There is an ongoing need to understand the cardiovascular effects of oncological treatments as cancer survivorship increases and competing non-cancer death becomes more likely.”

He concluded: “PRONOUNCE provides a model for the interdisciplinary collaboration between oncologists and cardiologists with a shared goal of evaluating the impact of cancer therapies on cardiovascular outcomes.”



Notes to editor

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This press release accompanies both a presentation and an ESC press conference at ESC Congress 2021. It does not necessarily reflect the opinion of the European Society of Cardiology.

Funding: The study was funded by Ferring Pharmaceuticals.

Disclosures: None.

References and notes

1PRONOUNCE: comparing cardiovascular safety of degarelix vs. leuprolide in patients with advanced prostate cancer and cardiovascular disease.

2Rawla P. Epidemiology of prostate cancer. World J Oncol. 2019;10:63–89.

3Leong DP, Fradet V, Shayegan B, et al. Cardiovascular risk in men with prostate cancer: insights from the RADICAL PC Study. J Urol. 2020;203:1109–1116.

4Sturgeon KM, Deng L, Bluethmann SM, et al.  A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J. 2019;40:3889–3897.

5Gunner C, Gulamhusein A, Rosario DJ, et al. The modern role of androgen deprivation therapy in the management of localised and locally advanced prostate cancer. J Clin Urol. 2016;9(2 Suppl):24–29.

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