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Have we mis-PRONOUNCEd the cardiovascular risk of GnRH agonists? A critical appraisal of the PRONOUNCE trial

Prostate Cancer and Prostatic Diseases volume 25, pages 657–658 (2022)Cite this article

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The association between androgen deprivation therapy (ADT) and cardiovascular (CV) risk is controversial, with trials demonstrating conflicting results [1, 2]. In a large, pooled analysis, Albertsen et al. reported a lower risk of CV events in men treated with GnRH antagonists compared to GnRH agonists (hazard ratio (HR), 0.44; 95% CI 0.26–0.74) [3]. Similarly, Shore et al. demonstrated a lower rate of CV events among men receiving relugolix (2.9%) compared to leuprolide (6.2%) (HR 0.46; 95% CI 0.24–0.88) [4]. However, neither trial had CV outcomes as a prespecified endpoint, with no predetermined criteria or blinding for participant enrollment with regards to CV risk factors. This led authors to deem their results hypothesis generating rather than practice changing [3].The PRONOUNCE trial, a prospective, randomized, multi-center study, was specifically designed and powered to compare CV morbidity, defined as the time to first major adverse cardiovascular event (MACE) within 12 months, between patients with pre- existing atherosclerotic CV disease receiving degarelix and leuprolide [5]. This study was powered assuming MACE rates of 5.1% and 10.2% for degarelix and leuprolide, respectively [3]. The trial was prematurely terminated due to slower than projected enrolment (545/900) and fewer than projected MACE (26/66). While the authors concluded that the relative CV safety of ADT approaches remained unresolved, we question whether the data reflects this. Thus, our aim was to assess if PRONOUNCE could actually achieve its stated aims and address this clinical question.

First, we performed a futility analysis by calculating the conditional probability of finding a significant difference in MACE rates between arms using trial data at time of termination. Second, we simulated scenarios to assess whether full accrual could have led to results consistent with assumptions made during study design (namely, of event rates and relative effects). To do so, a simulated model was created to estimate final hazard ratios (HRs) and event counts had the trial successfully recruited 900 patients, assuming various MACE rates in the additional patients. Finally, using MACE rates reported in the trial for the leuprolide arm as a baseline rate (4.1%) and assuming the same relative effect (HR = 0.49), we re-calculated the sample size necessary to achieve statistical significance. Calculations were conducted using PASS 2020.

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References

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Authors and Affiliations

  1. Division of Urology, University of Toronto, Toronto, ON, Canada

    Raj Tiwari, Katherine Lajkosz, Neil Fleshner & Christopher J. D. Wallis

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  1. Raj Tiwari
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  2. Katherine Lajkosz
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  3. Neil Fleshner
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  4. Christopher J. D. Wallis
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Contributions

RT: Project development, paper writing. KL: Data management, data analysis. NF: Project development, paper editing. CJDW: Project development, paper editing.

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Correspondence to Raj Tiwari.

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Tiwari, R., Lajkosz, K., Fleshner, N. et al. Have we mis-PRONOUNCEd the cardiovascular risk of GnRH agonists? A critical appraisal of the PRONOUNCE trial. Prostate Cancer Prostatic Dis 25, 657–658 (2022). https://doi.org/10.1038/s41391-021-00483-5

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