When Your Cancer Drug Affects Your Heart:
Cardiotoxicity risk in metastatic castration-resistant prostate cancer: enzalutamide versus abiraterone | Cardio-Oncology | Springer Nature Link
What Every Patient on Xtandi or Zytiga Needs to Know
Bottom Line Up Front (BLUF)
What You Need to Know Before Reading Further
- Both enzalutamide (Xtandi) and abiraterone (Zytiga/Yonsa) are effective and lifesaving treatments for advanced prostate cancer — neither should be stopped without a doctor's guidance.
- A landmark 2026 Medicare study of nearly 6,000 patients found that abiraterone carries a 12% higher overall risk of serious cardiac events (MACE) than enzalutamide, rising to 16% higher risk among patients with pre-existing heart disease.
- Abiraterone was associated with 73% greater risk of atrial fibrillation, 37% greater risk of blood clots (venous thromboembolism), and 13% higher all-cause mortality vs. enzalutamide in the same study.
- Three in four mCRPC patients already have cardiovascular disease before starting either drug — making heart risk an urgent conversation to have with your oncologist.
- If you have a history of heart failure, stroke, arrhythmia, or heart attack, ask your care team to explicitly discuss whether enzalutamide might be the more heart-safe option for your specific situation.
- Both drugs raise cardiovascular risk compared to no treatment. Enzalutamide carries a more modest but still real 10–22% increased cardiac risk over baseline.
- New AI-powered risk prediction tools may soon help doctors personalize cardiovascular monitoring before you start treatment.
Setting the Stage: Two Drugs, One Critical Question
If you or someone you love is being treated for metastatic castration-resistant prostate cancer (mCRPC), chances are very good you've heard of — or are taking — either enzalutamide (brand name Xtandi) or abiraterone acetate (brand names Zytiga or Yonsa). These two androgen receptor pathway inhibitors, known in the medical world as ARPIs, have transformed the treatment of advanced prostate cancer over the past decade. Both are approved by the FDA, recommended by every major oncology guideline, and widely regarded as cornerstones of care.
But both drugs also interact in important ways with the heart and blood vessels. And now, a rapidly converging body of real-world evidence — anchored by a major new study published in Cardio-Oncology in March 2026 — is drawing a clearer map of exactly where those risks differ, who faces the greatest danger, and what you can do about it.
Enzalutamide (Xtandi) is abbreviated throughout as ENZA. Abiraterone (Zytiga/Yonsa) is abbreviated as ABI. "mCRPC" refers to metastatic castration-resistant prostate cancer — cancer that has spread beyond the prostate and is no longer fully controlled by standard hormone therapy (ADT). "MACE" stands for Major Adverse Cardiovascular Events — a composite measure including heart attack, stroke, unstable angina, and heart failure.
The New Landmark Study: What It Found
The most comprehensive U.S. study to date on this topic, by Bryce et al. (2026), was published in Cardio-Oncology as an "Article in Press" in March 2026. It analyzed data from the Centers for Medicare & Medicaid Services (CMS) Medicare Fee-for-Service database — one of the largest patient registries in the world, covering more than 68 million Americans aged 65 and older.
The researchers identified 6,319 chemotherapy-naïve mCRPC patients aged 65 or older who started treatment with either ENZA or ABI between September 2014 and May 2017, then followed them through December 2022. After careful statistical matching to ensure the two groups were comparable in age, health status, and prior conditions, 5,826 patients (2,913 per group) were included in the final analysis. A notable 76% of patients — nearly three in four — had a documented history of cardiovascular disease before starting treatment.
The primary finding: ABI was associated with a statistically significant 12% higher risk of four-point MACE compared with ENZA. More striking were the differences in specific event types:
| Cardiovascular Outcome | ABI Risk vs. ENZA (Hazard Ratio) | Statistical Significance |
|---|---|---|
| Composite 4-point MACE | +12% higher (HR: 1.12) | P = 0.028 |
| Atrial Fibrillation | +73% higher (HR: 1.73) | P < 0.001 |
| Venous Thromboembolism (blood clots) | +37% higher (HR: 1.37) | P = 0.037 |
| Unstable Angina / Revascularization | +13% higher (HR: 1.13) | P = 0.041 |
| All-Cause Death | +13% higher (HR: 1.13) | P < 0.001 |
| Acute Myocardial Infarction | No significant difference (HR: 1.01) | P = 0.987 |
| Stroke | No significant difference (HR: 0.92) | P = 0.505 |
The results were confirmed in sensitivity analyses and held up when researchers used an alternative broader definition of cardiovascular events — showing a 20% higher risk for ABI-treated patients overall when that wider lens was applied.
The Heart Disease Subgroup: Where the Difference Gets Larger
One of the study's most clinically important findings is what happened when researchers separated patients by whether or not they had a history of cardiovascular disease.
Among patients with pre-existing cardiovascular disease (which, remember, was 76% of the study population), the differences widened considerably:
- +16% higher risk of composite MACE (HR: 1.16, P = 0.009)
- +89% higher risk of atrial fibrillation (HR: 1.89, P < 0.001)
- +47% higher risk of venous thromboembolism (HR: 1.47, P = 0.024)
- +16% higher risk of unstable angina/revascularization (HR: 1.16, P = 0.013)
- +14% higher risk of all-cause death (HR: 1.14, P < 0.001)
Among patients without prior cardiovascular disease, the researchers found no significant difference in cardiac event rates between the two drugs — though ABI was still associated with a 12% higher risk of death even in this healthier subgroup (HR: 1.12, P = 0.036).
"The increased risk of MACE with use of ABI is driven by pre-existing CVD... Treatments associated with lower CV event risk may be considered to improve outcomes in patients with pre-existing CVD."
— Bryce et al., Cardio-Oncology (2026)The study authors are careful to note that these results come with important caveats. The study was retrospective and observational, meaning it cannot prove that ABI caused the cardiac events — only that the two were associated. Patients who switched treatments during the follow-up period may have diluted the true effect size; the authors believe this means the real difference between the drugs is likely larger than reported. And since data was from 2014–2022, some of these patterns may have shifted with newer prescribing practices.
Why Might Abiraterone Carry More Cardiovascular Risk?
The mechanistic reasons behind the cardiac risk difference are an active area of investigation, but several plausible explanations have emerged in the medical literature:
1. Mandatory Corticosteroid Co-Administration
Abiraterone must be taken with prednisone (or another corticosteroid) to offset mineralocorticoid excess — a side effect of how the drug works. Corticosteroids are well-known to raise blood pressure, increase fluid retention, elevate blood glucose, and contribute to cardiovascular events when used chronically. Enzalutamide, which works by a different mechanism (blocking the androgen receptor rather than inhibiting testosterone synthesis), does not require co-administration of a corticosteroid. Multiple studies have identified this corticosteroid requirement as a likely contributing factor to ABI's higher cardiac risk profile.
2. Mineralocorticoid Effects
Abiraterone inhibits the enzyme CYP17A1, which is involved in the production of testosterone. This also disrupts the normal balance of mineralocorticoids — hormones that regulate blood pressure and electrolyte levels. Even with prednisone co-administration, Cancers (2025) research from Taiwan reports that studies consistently find a 31–77% increased cardiovascular risk with abiraterone compared to androgen deprivation therapy alone, attributed in part to these mineralocorticoid effects.
3. Known Adverse Drug Reaction Profile
Atrial fibrillation is listed in the official Zytiga prescribing information as a known adverse drug reaction. The Bryce et al. study's finding of a 73% higher atrial fibrillation risk with ABI versus ENZA is consistent with this labeling and with prior pharmacovigilance studies.
4. Abiraterone Is Not Uniquely Risky — Both Drugs Elevate Risk Over Baseline
It is important to underscore what the data do and don't say. Enzalutamide is not "safe" for the heart — it too raises cardiovascular risk above baseline. A 2022 Journal of the National Cancer Institute analysis of Medicare claims found that men on enzalutamide had a 22% higher risk of a major cardiovascular adverse event compared with men not receiving the drug. The cardiac risk difference is a relative one: ABI's risk is substantially higher than ENZA's risk, while ENZA's risk is meaningfully higher than no treatment.
A Consistent Signal Around the World
The Bryce et al. (2026) findings don't stand alone — they are the latest chapter in a rapidly growing international literature that has been telling a consistent story:
Hong Kong (2024)
A retrospective cohort study of 1,015 prostate cancer patients in Hong Kong, published in Prostate Cancer and Prostatic Diseases, found that enzalutamide users had significantly lower risks of four-point MACE, adverse cardiovascular events, myocardial infarction, and all-cause mortality compared with abiraterone users. The difference was especially pronounced in patients aged 65 and older.
Germany (2025)
The AVENGER study, published in Advances in Therapy (2025), examined more than 2,200 mCRPC patients in Germany and found a 30% higher risk of cardiovascular events with ABI compared to ENZA — alongside lower CV event rates, fewer recurrent events, and longer overall survival in the ENZA group.
Taiwan (2023 and 2025)
A 2023 study from Taiwan comparing the two drugs in chemotherapy-naïve mCRPC patients found an 80% lower MACE risk in the ENZA group (HR: 0.20), and a July 2025 machine learning study using the Taiwan Cancer Registry — covering 4,739 patients — identified five key cardiovascular risk factors that predict cardiac events in patients starting either drug: age under 65 or over 75, prior heart failure, stroke history, high blood pressure, and prior heart attack.
United States — Veterans Administration (2023)
A study of U.S. veterans with mCRPC, published in Prostate Cancer and Prostatic Diseases (2023), found that ENZA-treated patients had a median overall survival 2.1 months longer than ABI-treated patients overall. Among patients with pre-existing cardiovascular disease, ENZA-treated patients survived 3.3 months longer than ABI-treated counterparts.
United States — SEER-Medicare (2025)
A large study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, published in the Journal of Geriatric Oncology in early 2025, found that the one-year MACE risk was 5.5% for abiraterone initiators versus 3.6% for enzalutamide initiators. The difference was most pronounced in frail and prefrail patients, underlining the importance of frailty assessment when choosing between these drugs.
ASCO 2025 Meta-Analysis
At the 2025 American Society of Clinical Oncology Annual Meeting, a meta-analysis combining four studies and 9,444 patients presented a pooled finding: abiraterone carries a 58% greater risk of heart failure compared to enzalutamide in older mCRPC patients (relative risk 1.58, 95% CI: 1.11–2.26, P = 0.01).
- +58% Higher heart failure risk with ABI vs. ENZA (ASCO 2025 meta-analysis, 9,444 patients)
- +30% Higher CV event risk with ABI in German AVENGER study (2025)
- 2.1 mo Longer median survival with ENZA vs. ABI in U.S. Veterans study
- 5 factors Key CV risk predictors identified by AI study (Taiwan, 2025)
What ENZA Does to the Heart — It's Not Off the Hook Either
While the consistent direction of the evidence favors enzalutamide over abiraterone on cardiovascular outcomes, enzalutamide has its own real cardiovascular concerns that patients and doctors must weigh:
Hypertension: Both drugs are associated with elevated blood pressure, but ENZA has been specifically identified as significantly increasing hypertension risk in multiple meta-analyses. The 2025 Taiwan machine learning study identifies hypertension as one of the top five predictors of serious cardiac events in ARPI-treated patients.
Fatigue and falls risk: Enzalutamide carries a known risk of fatigue, dizziness, and — importantly — seizures in rare cases. Falls resulting in injury can have their own cardiac consequences in older men.
Memory and cognitive effects: NCCN guidelines note that grade 1–3 memory impairment occurs in up to 13% of patients on enzalutamide vs. 4% on comparator regimens in some trials. This can affect a patient's ability to monitor their own cardiac symptoms.
Baseline cardiac event risk still elevated: Men on ENZA face a 10–22% higher cardiovascular event risk compared to men with advanced prostate cancer not on any ARPI.
The Healthcare System Burden: More Hospital Visits with ABI
The Bryce et al. (2026) study also examined the real-world healthcare utilization implications of these cardiac differences. Rates of cardiovascular-related inpatient hospital visits were meaningfully higher in ABI-treated patients (28.0 per 100 patient-years) than ENZA-treated patients (22.2 per 100 patient-years) — a statistically significant difference. Cardiovascular-related outpatient visits also ran higher in the ABI group (26.0 vs. 23.9 per 100 patient-years).
The authors note this finding aligns with prior research showing higher healthcare utilization costs with ABI versus ENZA, and that the increased cardiac event burden translates directly into a meaningful and growing burden on both patients and the Medicare system.
What the Guidelines Say — and What They Don't
Current major treatment guidelines — including the AUA/SUO Advanced Prostate Cancer Guidelines and the NCCN Prostate Cancer Guidelines (Version 1.2025) — list both enzalutamide and abiraterone as equivalent "Strong Recommendation, Grade A" options for mCRPC. Neither guideline currently preferentially recommends one over the other specifically based on cardiovascular risk.
However, major oncology and cardiology societies are increasingly aware of this evidence gap. The European Society of Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Heart Failure Association of the European Society of Cardiology — working with the International Cardio-Oncology Society — have all called for pre-treatment cardiovascular evaluation for patients starting ARPIs. The 2025 Taiwan machine learning study was specifically motivated by this guidance gap, noting that existing cardiovascular risk calculators were "not specifically developed for PCa patients receiving androgen deprivation therapy."
What This Means for You Practically
The absence of a formal guideline preference for one drug over the other does not mean the cardiovascular risk differences are unimportant — it means the guidelines haven't yet fully caught up with the real-world evidence. This is the period where an informed, proactive patient conversation with your oncologist and cardiologist is most valuable.
The Bryce et al. study team explicitly states that the findings "can help guide treatment decisions for patients with mCRPC, including those at high risk of CV events." Their specific recommendation is that in patients with pre-existing cardiovascular disease — the majority of mCRPC patients — treatments associated with lower CV event risk should be actively considered.
Questions to Ask Your Doctor
Based on the totality of this evidence, here are some questions the IPCSG recommends discussing with your oncologist, cardiologist, or primary care physician:
Bring your full cardiac history — prior heart attacks, arrhythmias, heart failure, stents, bypass surgery, blood pressure history — to this conversation. The research is clear that prior CVD amplifies the risk differences between the two drugs.
Cardio-oncology is a growing subspecialty that specializes exactly in this overlap between cancer treatment and heart health. Major cancer centers increasingly offer this service.
Ask about frequency of blood pressure checks, EKGs, and whether your cardiac medications need to be adjusted before or during treatment.
Atrial fibrillation symptoms (racing or irregular heartbeat, shortness of breath, sudden fatigue, dizziness) and signs of blood clots (leg swelling, chest pain, shortness of breath) are especially important to know, as both risks are elevated with these treatments.
This is a reasonable conversation to have with your oncologist, particularly if you've experienced any cardiac events or worsening cardiac symptoms since starting treatment. Never stop any medication without medical supervision.
What's On the Horizon
Several important developments in this area are expected to shape clinical practice over the next few years:
Fine-particle abiraterone (Yonsa): A newer formulation that can be taken without food may have a somewhat different side effect profile than original Zytiga, though direct cardiac comparison data versus enzalutamide in large real-world populations are still limited.
AI-based risk prediction tools: The 2025 Taiwan machine learning study described above demonstrated that a five-factor model (age, prior heart failure, stroke history, hypertension, and prior heart attack) can predict serious cardiovascular events in ARPI-treated patients with greater than 85% accuracy. If validated in larger populations, this kind of tool could help personalize treatment selection before a single pill is taken.
Evolving guidelines: As the real-world evidence base continues to mature, it is increasingly likely that major guidelines will incorporate specific cardiovascular risk-stratification criteria into their ARPI selection guidance. IPCSG will report on these updates as they occur.
Newer ARPIs: Darolutamide (Nubeqa) and apalutamide (Erleada) are also ARPIs approved for certain stages of prostate cancer. While direct cardiac comparisons with enzalutamide and abiraterone in large real-world cohorts are still limited, darolutamide in particular has shown a favorable cardiac profile in its pivotal trials and may represent an option for high-cardiac-risk patients in appropriate settings.
Do not stop your medication without consulting your doctor. Both enzalutamide and abiraterone provide significant survival benefits. The cardiovascular risk differences described in this article must always be weighed against the profound anti-cancer benefits these drugs provide.
This article is for informational purposes only and does not constitute medical advice. Treatment decisions must always be made in partnership with your oncology team based on your individual clinical situation.
Note on study funding: The Bryce et al. (2026) lead study described in this article was funded by Astellas Pharma Inc. and Pfizer Inc. — the co-developers of enzalutamide. Most co-authors are employees of Astellas. This is a legitimate and common funding structure for pharmacoepidemiological research, but readers should be aware of it. Importantly, the study's findings are consistent with the independent, non-industry-funded literature from Hong Kong, Germany, Taiwan, and U.S. Veterans Administration databases described above.
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