Summary

• AKEEGA may cause hypertension. Preexisting hypertension should be adequately controlled before starting treatment.¹ Please refer to local labeling for additional considerations.
• AKEEGA may cause hypokalemia, fluid retention, and cardiovascular adverse reactions due to increased mineralocorticoid levels resulting from CYP17 inhibition.¹
  • Hypokalemia and fluid retention should be corrected and controlled prior to use.
  • QT prolongation has been observed in patients experiencing hypokalemia associated with treatment.
• AKEEGA should be used with caution in patients with a history of cardiovascular disease.¹
• In MAGNITUDE, the phase 3 study evaluating the efficacy and safety of AKEEGA with prednisone as first-line (L1) therapy in metastatic castration-resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2, cardiovascular events was reported as a treatment-emergent adverse event (TEAE).^2-5
  • At the first interim analysis (IA1):
    • Hypertension occurred in 31.1% and 20.9% of patients in the niraparib/abiraterone acetate with prednisone (AAP) and placebo/AAP groups, respectively, after a median follow-up of 18.6 months.³
    • Additional all grade cardiovascular TEAEs in the niraparib/AAP group vs the placebo/AAP group included arrhythmia (12.7% vs 5.7%), cardiac failure (1.9% vs 1.9%), and ischemic heart disease (1.9% vs 3.8%).⁶
    • Cardiovascular TEAEs reported in the HRR+ cohort are described in Table: Cardiovascular TEAEs (Occurring in >20% of Patients) in the MAGNITUDE HRR+ Cohort at IA1.
    • Cardiovascular TEAEs leading to dose reduction, discontinuation, or death are included in Table: Cardiovascular TEAEs Leading to Dose Reduction, Discontinuation, or Death in the MAGNITUDE HRR+ Cohort at IA1.
  • At the second interim analysis (IA2)⁴:
    • No new safety signals were observed.
    • Hypertension occurred in 33.0% and 22.3% of patients in the niraparib/AAP and placebo/AAP groups, respectively, as a common adverse event (AE) regardless of causality.
  • At the final analysis for overall survival (OS)⁷:
    • Cardiovascular TEAEs in the AKEEGA group vs the placebo/AAP group included hypertension (34.0% vs 23.2%), fluid retention/edema (17.0% vs 14.2%), hypokalemia (16.0% vs 10.4%), arrhythmia (13.2% vs 7.6%), ischemic heart disease (5.2% vs 4.7%), cerebrovascular disorders (3.3% vs 2.4%), and cardiac failure (2.8% vs 1.9%), respectively.
• In AMPLITUDE, the phase 3 study evaluating the efficacy and safety of AKEEGA with prednisone in patients with deleterious germline or somatic HRR gene-altered metastatic castration-sensitive prostate cancer (mCSPC; N=696), cardiovascular events were reported as TEAE.⁸ 
  • At the first interim analysis, cardiovascular TEAEs reported in the AKEEGA group vs the placebo/AAP group included hypertension (45% vs 33%), arrhythmia (20% vs 8%), and cardiac failure (6% vs 2%), respectively.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^3,4 and Efstathiou et al (2023)⁹ reported the efficacy and safety of AKEEGA with prednisone compared to placebo/AAP in mCRPC for patients with certain HRR mutations (n=423), including BRCA1/2 (n=225). Patients were randomized 1:1 to receive niraparib 200 mg by mouth (PO) once daily or matching placebo in combination with abiraterone acetate 1000 mg PO once daily plus prednisone 5 mg twice daily.

The study design is presented in Figure: MAGNITUDE Study Design.

• Patients were excluded if they had a history or evidence of any of the following conditions:
  • Severe or unstable angina, myocardial infarction or ischemia requiring coronary artery bypass graft or stent within the previous 6 months, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), clinically significant ventricular arrhythmias within 6 months prior to randomization, or NYHA Class II to IV heart disease.¹⁰
  • Uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg); however, those with a history of hypertension were allowed if BP was controlled to within these limits by antihypertensive treatment.¹⁰

Cardiovascular Events

• The median total duration of assigned treatment for the HRR+ cohort was 13.8 months in the niraparib/AAP group and 12.1 months in the placebo/AAP group.³
• At IA1, which occurred after a median follow-up of 18.6 months³:
  • All grade hypertension was reported as a TEAE that occurred in >10% of patients in either treatment group within the HRR+ cohort, with 31.1% and 20.9% in the niraparib/AAP and placebo/AAP groups, respectively. Grade 3 hypertension was reported in 14.6% and 12.3% in the niraparib/AAP and placebo/AAP groups, respectively.
  • Cardiovascular TEAEs from an additional follow-up were reported in Table: Cardiovascular TEAEs (Occurring in >20% of Patients) in the MAGNITUDE HRR+ Cohort at IA1.
  • Cardiovascular TEAEs leading to dose reduction, discontinuation, or death are included in Table: Cardiovascular TEAEs Leading to Dose Reduction, Discontinuation, or Death in the MAGNITUDE HRR+ Cohort at IA1.
• The safety profile at IA2 was consistent with that of IA1, with no new safety signals observed.⁴
  • Hypertension was among the most common (≥30%) AEs for niraparib/AAP vs placebo/AAP (33.0% vs 22.3%, respectively) regardless of causality.
  • The highest grade of hypertension observed was grade 3. There were no events of hypertensive crises or posterior reversible encephalopathy syndrome observed, and no patients discontinued treatment due to hypertension.

• At the final analysis for OS, the median follow-up was 37.3 months. Cardiovascular TEAEs of special interest are summarized in Table: Cardiovascular-Related TEAEs in the MAGNITUDE HRR+ Population at Final Analysis.
• Among TEAEs leading to death included acute myocardial infarction and myocardial infarction in the placebo/AAP group (0.9% each).

AMPLITUDE STUDY

Attard et al (2025) reported the efficacy and safety of AKEEGA plus ADT compared with placebo/AAP plus ADT in patients with deleterious germline or somatic HRR gene-altered mCSPC (N=696).⁸ 

The study design is presented in Figure: AMPLITUDE Study Design.

• Patient characteristics were well balanced between the 2 groups.

Cardiovascular Events

• A summary of cardiovascular events reported in both treatment arms is shown in Table: Cardiovascular TEAEs in the AMPLITUDE Study at IA1.

ADDITIONAL INFORMATION

Monitoring and Management

In the MAGNITUDE study, patients who developed nonhematologic drug-related grade 3 or higher toxicities were managed as follows, per protocol¹⁰:

• Treatment should be withheld unless appropriately managed per institutional standard.
• Treatment must not be reinitiated until symptoms of the toxicity have resolved to grade 1 or baseline.
• Patients with reported treatment-related hypertensive crisis were permanently discontinued.
• If dose reduction was used for AE management:
  • Only 1 dose-level reduction was permitted for niraparib (from 200 mg to 100 mg). If a patient was on a reduced dose of niraparib (100 mg daily), they were to be discontinued for nonhematologic drug-related grade ≥3 toxicities lasting continuously for more than 28 days.
• Please refer to local labeling for additional considerations.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 23 May 2025. Summarized in this response are relevant data limited to the phase 3 MAGNITUDE and AMPLITUDE studies in patients with mCRPC and mCSPC, respectively.