SUMMARY

• Hepatic toxicities are a known potential side effect of AKEEGA with prednisone and have been reported in patients taking AKEEGA.^1,2 Please refer to local labeling for additional considerations.
• 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, hepatotoxicity was reported as a treatment-emergent adverse event (TEAE).^3,4
  • Patients with active or symptomatic viral hepatitis or chronic liver disease (as evidenced by ascites, encephalopathy, or bleeding disorders secondary to hepatic dysfunction) were excluded from the study.¹
  • In the HRR+ population (cohort 1), hepatotoxicity was evaluated at the first interim analysis.⁵ Hepatotoxicity TEAEs leading to dose reduction or discontinuation reported in the first interim analysis are described in Table: Treatment-Emergent Hepatotoxicity Events Leading to Dose Reduction or Discontinuation in Cohort 1 (HRR+).
  • At the second interim analysis, hepatotoxicity was reported in 27 (12.7%) patients in the niraparib/abiraterone acetate with prednisone (AAP) group and 27 (12.8%) patients in the placebo/AAP group. Grade 3 events occurred in 3 (1.4%) and 10 (4.7%) patients in the niraparib/AAP and placebo/AAP groups, respectively. Grade 4 acute hepatitis occurred in 1 patient in the niraparib/AAP group. Serious adverse events (AEs) occurred in 2 (0.9%) patients in the niraparib/AAP group, 1 of whom discontinued treatment due to acute hepatitis.²
  • In HRR+ patients receiving niraparib/abiraterone acetate (AA) dual-action tablet (DAT) with prednisone (cohort 3), hepatotoxicity was reported in 7 (7.4%) patients. Two patients experienced a grade 3 event. No patients had grade 4/5 events or serious AEs.²
  • Treatment-emergent hepatotoxicity events reported in the second interim analysis are described in Table: Treatment-Emergent Hepatotoxicity Events at IA2 in Cohort 1 (HRR+) and Table: Treatment-Emergent Hepatotoxicity Events at IA2 in Cohort 3.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^3,4 and Efstathiou et al (2023)⁶ 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.

MAGNITUDE Study Design^1,3,7

Abbreviations: AA, abiraterone acetate; AML, acute myeloid leukemia; AR, androgen receptor; BPI-SF, Brief Pain Inventory-Short Form; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; GnRHa, gonadotropin-releasing hormone analog; HRR, homologous recombination repair; L1, first-line therapy; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging; NIRA, niraparib; nmCRPC, non-metastatic castration-resistant prostate cancer; ORR, objective response rate; OS, overall survival; PARPi, poly ADP-ribose polymerase inhibitor; PBO, placebo; PFS2, progression-free survival on first subsequent therapy; PO, orally; PSA, prostate-specific antigen; R, randomization; rPFS, radiographic progression-free survival; TCC, time to cytotoxic chemotherapy; TSP, time to symptomatic progression; TTPP, time to PSA progression.
^aNovel second-generation AR-targeted therapy such as enzalutamide, apalutamide, or darolutamide; taxane-based chemotherapy; or >4 months of AAP before randomization.

• Patients with active or symptomatic viral hepatitis or chronic liver disease (as evidenced by ascites, encephalopathy, or bleeding disorders secondary to hepatic dysfunction) were excluded.¹
• All patients received a gonadotropin releasing hormone analog (GnRHa) or bilateral orchiectomy.¹
• 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

Hepatotoxicity Events

• AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.¹
• Hepatic toxicities known to be associated with treatment with AAP were not worsened with the addition of niraparib.²
• Hepatotoxicity TEAEs leading to dose reduction or discontinuation in HRR+ patients (cohort 1) that were reported in the first interim analysis, at a median follow-up of 18.6 months, are described in Table: Treatment-Emergent Hepatotoxicity Events Leading to Dose Reduction or Discontinuation in Cohort 1 (HRR+). The median treatment duration was 13.8 months in the niraparib/AAP group and 12.1 months in the placebo/AAP group.³

Treatment-Emergent Hepatotoxicity Events Leading to Dose Reduction or Discontinuation in Cohort 1 (HRR+)^8a

• In cohort 1 at the second interim analysis, hepatotoxicity was reported in 27 (12.7%) patients in the niraparib/AAP group and 27 (12.8%) patients in the placebo/AAP group.² Hepatic laboratory abnormalities are described in Table: Treatment-Emergent Hepatotoxicity Events at IA2 in Cohort 1 (HRR+). The median treatment duration was 17.9 months and 15.2 months in the niraparib/AAP and placebo/AAP groups, respectively.²
  • Grade 3 events occurred in 3 (1.4%) and 10 (4.7%) patients in the niraparib/AAP and placebo/AAP groups, respectively. Most events resolved with interruption or dose reduction of abiraterone acetate.
  • Grade 4 acute hepatitis occurred in 1 patient in the niraparib/AAP group. There were no grade 5 events in either treatment group.
  • Serious AEs occurred in 2 (0.9%) patients in the niraparib/AAP group, 1 of whom discontinued treatment due to acute hepatitis, and the other had increased liver enzymes in the context of new liver lesions and progressive disease. One (0.5%) patient in the placebo/AAP group had a serious AE of hepatic failure due to liver lesions and progressive disease.
  • The median time to onset of hepatotoxicity was 34 days in the niraparib/AAP group and 56 days in the placebo/AAP group.

Treatment-Emergent Hepatotoxicity Events at IA2 in Cohort 1 (HRR+)^2a,b

• In HRR+ patients receiving niraparib/AA DAT with prednisone (cohort 3, n=95), at the second interim analysis, with a median treatment duration of 12.8 months, hepatotoxicity was reported in 7 (7.4%) patients.² Hepatic laboratory abnormalities are reported in Table: Treatment-Emergent Hepatotoxicity Events at IA2 in Cohort 3.
  • Grade 3 events occurred in 2 patients, of whom 1 patient had a history of hepatic steatosis and hepatomegaly and developed new metastatic liver lesions, and the other patient had hepatorenal failure in the context of progressive disease with death occurring 2 days later.
  • No patients had grade 4/5 events or serious AEs.
  • The median time to onset of hepatotoxicity was 57 days.

Treatment-Emergent Hepatotoxicity Events at IA2 in Cohort 3^2a,b

Additional information

Monitoring and Management

• Hepatic toxicities are a known potential side effect of AKEEGA.¹ Please refer to local labeling for additional considerations, such as dose modifications.
• Liver function tests (LFTs) should be performed prior to treatment and every 2 weeks for the first 3 cycles of treatment.¹
• During dose interruptions, LFTs should be monitored at least weekly. For patients being retreated, serum transaminases should be monitored at a minimum of every 2 weeks for 3 months and monthly for the next 3 months.¹
• If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases should be measured immediately.¹
• If a patient develops severe hepatotoxicity (ALT ≥20 x ULN) anytime while receiving abiraterone acetate (AA), they should be discontinued from treatment and retreatment with AA should not be attempted.¹
• Re-escalation of AA or niraparib is not permitted if the dose reduction was due to elevated LFTs.¹
• Patients who develop a concurrent elevation of ALT >3 x ULN and a total bilirubin >2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation should be permanently discontinued from treatment.¹

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