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The addition of androgen receptor signaling inhibitors (ARSIs) alongside standard androgen deprivation therapy (ADT) in advanced prostate cancer was associated with a significantly increased risk of adverse heart events, a systematic review and meta-analysis showed.

Across 24 randomized trials involving patients with locally advanced or metastatic disease, ARSI therapy was associated with a 75% higher risk of any-grade cardiovascular (CV) events (risk ratio [RR] 1.75, 95% CI 1.50-2.04, P<0.001), reported Ashwin Sachdeva, MBBS, PhD, of the University of Manchester in England, and colleagues.

And the addition of ARSI therapy was associated with a more than twofold higher risk of grade 3 or higher CV events (RR 2.10, 95% 1.72-2.55, P<0.001) and CV-related death (RR 2.02, 95% CI 1.32-3.10, P=0.001), according to findings published in .

"These results suggest that patients with prostate cancer should be advised about and monitored for the potential of increased risk of CV events with initiation of ARSI therapy alongside conventional hormonal therapy," the researchers wrote.

"As use of combination therapy becomes more widespread, particularly in earlier disease settings," Sachdeva and co-authors added, "there is greater need to evaluate and optimize baseline CV risk prior to commencing ARSI therapy," a class of drugs that includes abiraterone acetate (Zytiga), apalutamide (Erleada), darolutamide (Nubeqa), and enzalutamide (Xtandi).

The findings "are a call to action in the medical community," wrote Katelyn Atkins, MD, PhD, and Andriana Nikolova, MD, PhD, both of Cedars Sinai Medical Center in Los Angeles, in a . They added that the data "challenge us to reexamine current CV risk estimation models which omit active cancer and certain cancer therapeutics as potent CV risk modifiers."

They emphasized that spreading an awareness of this heightened risk should be a priority among primary care, urology, oncology, and cardio-oncology physicians to help protect prostate cancer survivors from avoidable CV morbidity.

Collectively with other research, Atkins and Nikolova suggested, the findings support two "fundamental" recommendations -- that all patients with prostate cancer have a baseline CV risk assessment performed (and repeated annually), and that stringent guideline-directed risk mitigation "should be used early and consistently."

"Such strategies include guideline-directed statin therapy, aggressive blood pressure control, heart-healthy diet with regular aerobic exercise to maintain optimal weight, muscle mass, and minimize central adiposity," they wrote.

As background, Sachdeva and colleagues pointed out that adverse CV events are a known risk of ADT, and that while adding ARSI agents to traditional ADT has improved survival, prostate cancer patients using combination therapies "are exposed to an increased period of intense androgen deprivation."

"Therefore, there is a greater need to better understand the risk of CV toxic effects with combination therapy," the study authors explained.

Their meta-analysis included 24 randomized controlled trials (most placebo-controlled) involving 22,166 men. Median ages in the trials ranged from 63 to 77 years, with median follow-up ranging from 3.9 to 96 months.

Eligible studies evaluated the addition of ARSIs (abiraterone, enzalutamide, apalutamide, and darolutamide) to standard of care ADT for men with M0 hormone-sensitive prostate cancer (HSPC; three trials with 2,171 patients), M1 HSPC (nine trials, 8,994 patients), M0 castrate-resistant prostate cancer (CRPC; three trials with 4,256 patients), or M1 CRPC (nine trials, 6,745 patients).

Addition of an ARSI increased the risk of all-grade and grade 3 or higher CV events across all disease states, the authors found.

Regarding specific CV events, ARSI therapy also was associated with an increased risk for grade 3 or higher hypertension, acute coronary syndrome, cardiac dysrhythmia, and cerebrovascular events (P<0.01 for all), but not venous thromboembolism:

• Hypertension: RR 2.25 (95% CI 1.74-2.90)
• Acute coronary syndrome: RR 1.93 (95% CI 1.43-1.60)
• Cardiac dysrhythmia: RR 1.64 (95% CI 1.23-2.17)
• Cerebrovascular events: RR 1.86 (95% CI 1.34-2.59)
• Venous thromboembolism: RR 0.84 (95% CI 0.61-1.16)

The study also "highlights the potential variation in CV events among different therapeutic antiandrogenic drug combinations," observed Sachdeva and colleagues.

Specifically, they found that the highest CV event rate occurred with the addition of the combination of abiraterone and enzalutamide (RR 2.92, 95% CI 2.59-3.30) followed by enzalutamide (RR 1.93, 95% CI 1.47-2.54), while the lowest CV event rate was with darolutamide (RR 1.30, 95% CI 1.09-1.54).

The researchers acknowledged several limitations to their work, including the "substantial heterogeneity" across trials, possibly explained by variations in the collection of adverse event data, follow-up frequency, and follow-up durations between trials. They also noted that CV outcomes were not consistently prespecified across studies "which may potentially bias measurement of these outcomes."

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