CV safety of degarelix vs leuprolide: Results remain inconclusive

In men with prostate cancer and concomitant atherosclerotic cardiovascular disease (ASCVD), major adverse cardiovascular event (MACE) incidence did not differ between those who were treated with degarelix or leuprolide, according to findings of the PRONOUNCE trial.

“[N]o difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed,” remarked principal investigator Professor Renato Lopes from Duke University Medical Center, Durham, North Carolina, US, at ESC 2021.

However, due to the premature termination of enrolment and fewer than expected participants and MACE numbers, “the relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists and agonists remains unresolved,” he added.

This international, prospective, open-label trial included 545 patients (median age 73 years) with prostate adenocarcinoma and ASCVD. They were randomized 1:1 to receive androgen deprivation therapy (ADT) in the form of either the GnRH antagonist degarelix (subcutaneous 240 mg starting dose followed by 80 mg dose every 28 days) or GnRH agonist leuprolide (intramuscular 22.5 mg every 84 days) for 12 months. Almost 50 percent of patients had localized prostate cancer, while 26.3 and 20.4 percent had locally advanced and metastatic disease, respectively. Median testosterone and prostate-specific antigen levels at baseline were 330 and 12.83 ng/dL, respectively.

The first adjudicated MACE event (myocardial infarction [MI], stroke, or all-cause death) over the 12-month period did not significantly differ between patients who received degarelix or leuprolide (5.5 percent vs 4.1 percent; hazard ratio [HR], 1.28, 95 percent confidence interval [CI], 0.59–2.79; p=0.53). [ESC 2021, Hot Line session; Circulation 2021;doi:10.1161/CIRCULATIONAHA.121.056810]

Inclusion of unstable angina requiring hospitalization in the primary outcome revealed similar findings (6.2 percent vs 5.6 percent; HR, 1.07, 95 percent CI, 0.53–2.13; p=0.86).

The incidence of a composite of cardiovascular death, non-fatal MI, or non-fatal stroke was rare and similar between the degarelix and leuprolide groups (n=9 vs 7; HR, 1.20; p=0.71).

Disease progression occurred in a comparable proportion of degarelix and leuprolide recipients (n=24 vs 27; HR, 0.89). At day 336, sustained castration (testosterone level <50 ng/dL) was also similar between groups (93.6 percent vs 94.8 percent), though profound castration (<20 ng/dL) was more likely in degarelix than leuprolide recipients (80.0 percent vs 67.8 percent; p=0.0003).

Severe adverse event (AE) incident rate was comparable between the degarelix and leuprolide groups (21.5 percent vs 20.4 percent). Injection-site reactions were more common with degarelix than leuprolide (60.4 percent vs 26.8 percent), as was fatigue (18.2 percent vs 12.6 percent), while hot flashes were more common with leuprolide (44.6 percent vs 38.9 percent). Thirteen and 11 patients in the degarelix and leuprolide groups, respectively, discontinued treatment due to AEs (4.7 percent vs 4.1 percent).

PRONOUNCEd Implications

“ASCVD is the leading cause of non-cancer deaths in men with prostate cancer [and] ADT is the pillar of treatment for patients with prostate cancer,” the authors said. “Understanding the impact of ADT therapy on cardiovascular risk is critical because many of the risk factors associated with prostate cancer are also associated with CVD.”

“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,” highlighted Lopes.

Lopes and co-authors called for greater awareness on managing risk factors for CVD which could lead to a lower number of events in prostate cancer patients, and consequently improved survival.

Lopes also noted the importance of multidisciplinary management in this context. “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,” he said.