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 BRCA1/2^2-5:
  • 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 New York Heart Association (NYHA) Class II to IV heart disease were excluded.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
  • Efficacy and safety analyses were not specifically reported for patients with baseline cardiovascular comorbidities in the MAGNITUDE study.
  • At the first interim analysis (IA1):
    • All grade 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 Grade 3 hypertension was reported in 14.6% and 12.3% in the niraparib/AAP and placebo/AAP groups, respectively.
    • Cardiovascular treatment-emergent adverse events (TEAEs) from an additional follow-up were reported in Table: Cardiovascular TEAEs (Occurring in >20% of Patients) in the MAGNITUDE HRR+ Cohort at IA1.
  • At the second interim analysis (IA2)⁴:
    • No new safety signals were observed at a median exposure of 17.9 months in the niraparib/AAP arm.
    • All grade 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. The highest grade of hypertension observed was grade 3, which was observed in 15.6% vs 12.3% of patients receiving niraparib/AAP vs placebo/AAP, respectively.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^3,4 and Efstathiou et al (2023)⁷ 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
• The study design is presented in Figure: MAGNITUDE Study Design.

Results

Patient Characteristics

• Baseline characteristics were broadly comparable between treatment arms; however, rates of visceral metastases, bone metastases, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 were imbalanced to the disadvantage of the niraparib/AAP group.³

Efficacy and Safety

• Efficacy and safety analyses were not specifically reported for patients with baseline cardiovascular comorbidities in the MAGNITUDE study.
• At IA1, which occurred after a median follow-up of 18.6 months:
  • 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.³ 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.
• At IA2, with a median exposure of 17.9 months in the niraparib/AAP arm⁴:
  • The safety profile was consistent with that of IA1, with no new safety signals observed.
  • All grade 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, which was observed in 15.6% vs 12.3% of patients receiving niraparib/AAP vs placebo/AAP, respectively.
  • There were no events of hypertensive crises or posterior reversible encephalopathy syndrome observed, and no patients discontinued treatment due to hypertension.

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