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
• MAGNITUDE is a 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.^2-5
  • Patients with a history of 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 were excluded from the MAGNITUDE study.⁶
  • Patients with uncontrolled hypertension (persistent systolic blood pressure [BP] ≥160 mmHg or diastolic BP ≥100 mmHg) were also excluded; however, those with a history of hypertension were allowed if BP was controlled to within these limits by antihypertensive treatment.⁶
  • 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 treatment-emergent adverse events (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%).⁷
    • 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.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^3,4 and Efstathiou et al (2023)⁸ 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 with prednisone 5 mg twice daily. 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.⁶
• Uncontrolled hypertension (persistent systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg).⁶

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.

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 protocol⁶:

• 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 16 July 2024. Summarized in this response are relevant data limited to the phase 3 MAGNITUDE study in patients with mCRPC.