CV safety of prostate cancer therapies 'remains unresolved': PRONOUNCE - Healio
August 30, 2021
3 min read
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Lopes RD, et al. Hot Line: PRONOUNCE. Presented at: European Society of Cardiology Congress; Aug. 27-30, 2021 (virtual meeting).
Disclosures: PRONOUNCE was sponsored by Ferring Pharmaceuticals. Lopes reports research contracts with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer and Sanofi and consultant fees, royalties and/or is owner/stockholder in Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck and Portola. Suter reports receiving grant support from Amgen.
In the PRONOUNCE trial, which aimed to compare the CV safety of androgen deprivation therapies for prostate cancer, there was no difference in major adverse CV events at 1 year among adults with prostate cancer and atherosclerotic CVD.
The trial was terminated early due to a smaller number of participants enrolled than planned and no difference in the rate of CV events at 1 year after assignment to degarelix (Firmagon, Ferring Pharmaceuticals) or leuprolide, Renato D. Lopes, MD, MHS, PhD, professor of medicine at Duke University School of Medicine and member of the Duke Clinical Research Institute, said during a presentation at the European Society of Cardiology Congress.
"The relative cardiovascular safety of [gonadotropin-releasing hormone] antagonists compared with agonists remains unresolved," Lopes said during a press conference.
Androgen deprivation therapy and CV risk
Leuprolide is a gonadotropin-releasing hormone (GnRH) agonist and degarelix is a GnRH antagonist. GnRH agonists are the most commonly used agents to treat prostate cancer; however, use of this therapy has been associated with CV events, potentially related to destabilization of atherosclerotic plaque. The researchers hypothesized that GnRH antagonists may confer a more favorable CV profile.
"PRONOUNCE is the first dedicated, global, randomized trial with blinded adjudication of cardiovascular outcomes in patients with prostate cancer," Lopes said at the press conference.
Enrollment was slower than projected and the trial was stopped early before accrual of the 900 planned participants.
Lopes reported primary results from 545 patients enrolled from May 2016 to April 2020 at 113 sites in 12 countries. All patients had prostate cancer and confirmed ASCVD, which was defined as prior MI; previous revascularization of carotid, coronary or iliofemoral arteries; greater than 50% stenosis in these vessels; or peripheral artery disease with an ankle brachial index of less than 0.9.
The median age was 73 years. At baseline, the median prostate-specific antigen level was 12.83 ng/dL. Half of those enrolled had localized prostate cancer, 26% locally advanced disease and 20% metastatic disease.
Patients were randomly assigned to receive a subcutaneous starting dose of degarelix 240 mg with 11 maintenance doses of 80 mg every 28 days or to receive an intramuscular injection of leuprolide 22.5 mg with three additional injections every 84 days. A cardiologist ensured optimal secondary prevention medications for ASCVD, according to the trial design.
The primary outcome was time to first adjudicated major adverse CV event, which included MI, stroke or death. The primary outcome occurred in 5.5% of the patients assigned degarelix compared with 4.1% of those assigned leuprolide (15 events vs. 11 events; HR = 1.28; 95% CI, 0.59-2.79; P = .53).
An expanded primary endpoint that also included angina requiring hospitalization demonstrated no difference between the two groups (HR = 1.07; 95% CI, 0.53-2.13).
Disease progression occurred in 27 patients assigned leuprolide and 24 assigned degarelix (HR = 0.89; 95% CI, 0.51-1.54).
Adverse events were similar between groups.
The results were simultaneously published in Circulation.
Need for cross-specialty collaboration
The PRONOUNCE trial involved close collaboration between cardiologists, oncologists and urologists.
"There is a need for rigorously-conducted cardio-oncology trials to better define the cardiovascular risk of new cancer agents," Lopes said. "PRONOUNCE provides a model for interdisciplinary collaboration among urologists, oncologists and cardiologists with a shared goal of evaluating the impact of cancer therapies on cardiovascular outcomes."
Discussing the trial results, Thomas M. Suter, MD, head of the department of internal medicine at Lindenhof Group Bern and cardio-oncology at University Hospital Bern, Switzerland, stressed the need for cross-specialty collaboration in cardio-oncology trials.
The PRONOUNCE trial "is a very collaborative effort and it's exactly what we need in cardio-oncology. But, in the end, unfortunately, it's a nonconclusive trial. The hypothesis-generating assumption was probably a little too optimistic.
"It's fair to say that androgen deprivation therapy may increase the risk for cardiovascular mortality and morbidity — not only short-term, but long-term — and we should keep this in mind. We don't know if GnRH agonists and antagonists have a different risk profile. It's very important that we identify patients at risk. We need to do personalized surveillance and treatment protocols for patients at risk with prostate cancer. I can't stress this enough: We need collaboration between the oncologists, urologists and the cardiovascular specialists," Suter said.
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