Newer Prostate Cancer Agents Not Free of Heart Risk

An increased risk of early death was observed in advanced prostate cancer patients with a history of cardiovascular disease (CVD) starting on abiraterone acetate (Zytiga) or enzalutamide (Xtandi), a retrospective population-based study found.

Compared to men without a history of CVD, those with three or more cardiac conditions had an increased risk of all-cause mortality at 6 months with these agents (relative risk 1.56, 95% CI 1.29-1.88) and was seen in both the pre- and post-chemotherapy setting, reported Grace Lu-Yao, PhD, MPH, of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, and colleagues.

The increased risk of early death was also observed in men with one or two CV conditions, though to a lesser degree (RR 1.16, 95% CI 1.00-1.36), they reported in European Urology.

Clinical trials typically exclude patients with significant medical problems, and in trials for prostate cancer drugs these can include men with uncontrolled hypertension or a history of major heart conditions such as severe angina, heart failure, or a recent myocardial infarction (MI).

"In the pivotal trial, they usually try to stick with patients who are healthy, but once it's approved they're pretty much used for everyone," Lu-Yao told MedPage Today.

For their study, Lu-Yao's group used Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data and found that two-thirds of prostate cancer patients treated with these second-generation antiandrogen agents had a pre-existing cardiac condition.

With abiraterone in the post-chemotherapy setting, 24% of patients in the SEER database had died within the first 6 months versus 17% in the drug's pivotal trial. With enzalutamide these rates were 28% versus 12%, respectively.

Preliminary findings from the study that only examined the abiraterone group were presented at the 2019 American Association for Cancer Research meeting in Atlanta.

'What's Your Alternative?'

When reached for comment, Christopher Anderson, MD, of NewYork-Presbyterian and Columbia University Medical Center in New York City, called the research "thought-provoking" and pointed out that use of these newer antiandrogens is likely to become ubiquitous in the treatment of prostate cancer as they get pushed earlier and earlier in the course of the disease.

He said that the research raises an important question and should spur further research to gather more data, but was unsure whether the current findings would have an impact on clinical practice.

"The question is, what's your alternative?" said Anderson, who was not involved in the study. He said that without any head-to-head trials, whether or not other newer-generation antiandrogens such as apalutamide (Erleada) and darolutamide (Nubeqa) are any safer won't be known for a number of years.

But if a patient with three or more cardiac conditions -- or other cardiac risk factors such as hypertension or diabetes -- walked into the clinic and enzalutamide and abiraterone were indicated for their disease, the findings potentially call for involvement of an internist or cardiologist to evaluate the patient's cardiac function and to try and optimize the new therapy, he said.

Drug-Drug or Drug-Disease?

Lu-Yao and colleagues also examined risk of hospitalizations by looking at hospital use in the 6 months before and after starting abiraterone or enzalutamide. In patients already treated with chemotherapy, those with one or two CV conditions on either drug had a higher risk of hospitalization compared to those without (incidence rate ratio 1.43, 95% CI 1.15-1.78).

In the post-chemotherapy setting alone, neither agent was significantly associated with increased hospitalizations. But in the chemotherapy-naive abiraterone group, there were significant increases in the risk of hospitalization among patients without a history of cardiac conditions (IRR 1.54, P<0.001) as well as for those with specific pre-existing heart conditions:

• Acute MI: IRR 1.55 (P=0.002)
• Atrial fibrillation (Afib): IRR 1.34 (P=0.001)
• Chronic heart failure: IRR 1.48 (P<0.001)
• Stroke: IRR 1.52 (P<0.001)
• Ischemic heart disease: IRR 1.50 (P<0.001)

"We show that there's significant increase in post-treatment hospitalization after abiraterone," Lu-Yao said. "The same pattern was not observed for enzalutamide."

Among patients treated earlier in their disease setting (before chemotherapy) and with three or more CV conditions, those on enzalutamide had a lower risk of hospitalization than those on abiraterone (rate ratio 0.59, 95% CI 0.44-0.79).

In their paper, Lu-Yao's group hypothesized that drug-drug or drug-disease interactions could be at play.

"Is abiraterone for some reason any riskier than enzalutamide? No one really knows," said Anderson. "I don't think that there's any great data on that, but they do work through different mechanisms."

While enzalutamide is an inhibitor of testosterone binding, abiraterone works by preventing testosterone synthesis, he explained, and said that at least theoretically it's possible that one mechanism could have more interactions with other drugs. Anderson said that if this were indeed the case, considerations for a new prostate cancer patient with cardiac conditions starting on one of these agents might require a bigger team that included a pharmacist and/or cardiologist in order to provide as much safety as possible.

The researchers looked at 2,845 prostate cancer patients treated with abiraterone and 1,031 treated with enzalutamide from 2011 to 2014. Most patients in the chemotherapy-exposed group were treated with abiraterone or enzalutamide in 2011-2012, when the agents were approved in a later-line setting, while the chemotherapy-naive group was largely treated with these agents in 2013-2014.

Two-thirds of patients had at least one preexisting CVD, the most common of which was ischemic heart disease (58.5%), followed by chronic heart failure (32.1%), Afib (18.8%), stroke (13.4%), and acute MI (6.0%). In all, 17.6% of the entire cohort had three or more CV conditions. Other comorbidities included hypertension in at least 80% and diabetes in about 40%.

In the post-chemotherapy setting, patients with hypertension were found to have a higher rate of hospitalization (IRR 1.38, 95% CI 1.15-1.78).

Of the 3,876 patients, 69.0% had localized or regional disease and about one-fourth (24.3%) had metastatic disease -- the remaining were unknown.

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