CV safety of prostate cancer therapies ‘remains unresolved’: PRONOUNCE
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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.
Reference:
Perspective
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Salim Hayek, MD, FACC
The design and conduct of a clinical trial focused on the adverse CV effects of a cancer trial is the major highlight of this study. The CV effects of cancer therapy have long been a secondary focus in cancer trials; with inadequate adjudication of events and lack of detail in characterizing the CV side effects of cancer therapy. It is great to finally witness a collaborative group of researchers run a cancer trial (PRONOUNCE) focused on CV events; notably with a class that has been reported to have some CV concern like androgen deprivation therapies.
Unfortunately, the trial did not reach its stated enrollment goal, precluding deriving strong conclusions. The lack of power is not surprising. The enrollment goal is based on an assumed event rate of 10% in the first year, using a composite endpoint of MI, stroke and death, which likely is an aggressive estimate.
The composite endpoint assumes a similar pathophysiology of events. While in general overlap exists in the pathophysiology of MI and stroke, this assumption may be weaker are attributed to cancer therapy, which often impacts the CV system in unusual ways.
These issues exemplify the challenge of research in cardio-oncology: CV events, while not rare, are infrequent. Moreover, older patients with a larger burden of CV comorbidities are more frequently being treated for cancer, who are likely to experience CV events unrelated to the cancer therapy. Determining whether events are related to the drug as opposed to a patient’s underlying pretreatment risk factors or disease is often impossible, and thus large sample sizes are needed in order to make inferences on associations of cancer drugs with CV events. Unfortunately, large sample sizes make clinical trials quite costly and difficult to fund.
Solutions to these challenges would be to embed detailed CV event characterization and adjudication in clinical trials of patients with cancer and the creation of cross-disciplinary multicenter registries (or modifying current registries) to include CV data. Given CV risk factors are rarely defining comorbidities in the selection of cancer therapies, reliable inferences could be made using observational data from these registries through clinical trial emulation.
Overall, PRONOUNCE is in achievement, even if it did not achieve its specified goals. The breaking down of silos and cross-disciplinary collaboration in this trial is an example to follow for future studies addressing CV effects of cancer therapy.
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Lopes RD, et al. Hot Line: PRONOUNCE. Presented at: European Society of Cardiology Congress; Aug. 27-30, 2021 (virtual meeting).
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