Comparison of AKEEGA with ZYTIGA

SUMMARY

• AKEEGA is a combination of niraparib, a poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi), and abiraterone acetate, an inhibitor of the enzyme 17-α-hydroxylase/C17,20-lyase (CYP17).¹
  • Niraparib is an orally available, highly selective PARPi with potent activity against the PARP-1 and PARP-2 deoxyribonucleic acid (DNA) repair polymerases.
  • Abiraterone acetate, the active ingredient of ZYTIGA, is a prodrug that is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that selectively inhibits NCYP17. CYP17 is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.²
• MAGNITUDE (NCT03748641) is a phase 3, randomized, double-blind, placebo-controlled, global study that evaluated the efficacy and safety of AKEEGA + prednisone compared with placebo/abiraterone acetate with prednisone (AAP) as first-line (L1) therapy in metastatic castration-resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2. The primary endpoint is radiographic progression-free survival (rPFS).^1,3-8
  • Patients were prospectively allocated to cohort 1 or 2 based on prescreening for HRR+ or HRR- status and subsequently randomized to receive niraparib or matching placebo in combination with AAP.
  • Prespecified endpoint results are described in Table: Prespecified Primary and Key Secondary Endpoints.
    • At the first interim analysis (IA1)⁴:
      • In patients with BRCA1/2 mutations, after a median follow-up of 16.7 months, a statistically significant improvement in median rPFS as assessed by blinded independent central review (BICR) was observed in the niraparib/AAP vs placebo/AAP group: 16.6 vs 10.9 months (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P=0.001).
    • At the final analysis⁸:
      • After a median follow-up of 37.3 months, no difference in overall survival (OS) between niraparib/AAP and placebo/AAP was observed in the HRR+ population (HR, 0.931; 95% CI, 0.720-1.203; P=0.585); however, in the BRCA1/2 subgroup, the median OS favored the niraparib/AAP group compared with the placebo/AAP group: 30.36 months vs 28.55 months (HR, 0.788; 95% CI, 0.554-1.120).
  • A summary of treatment-emergent adverse events (TEAEs) at final analysis is described in Table: Safety Summary: Final Analysis (HRR+ Population). In the niraparib/AAP vs placebo/AAP group, grade 3-4 adverse events (AEs) were reported in 157 (74.1%) vs 108 (51.2%) patients and TEAEs leading to discontinuation were reported in 18.4% vs 8.1% of patients, respectively.^7,8 Safety profiles at the final analysis and second interim analysis (IA2) were consistent with those observed at IA1, with no new safety signals reported.⁷
  • Additional analyses of the MAGNITUDE study have been conducted.^9-15
  • Ye et al (2026)¹⁶ conducted a subgroup analysis of AKEEGA + prednisone in the Asian HRR+ subgroup of the MAGNITUDE trial, focusing on BRCA+ patients. In the BRCA+ subgroup, median follow-up was 34.9 months (31.3 vs 37.0 months), and BICR-assessed median rPFS was 38.7 vs 8.3 months (HR, 0.33; 95% CI, 0.13-0.83; nominal P=0.0141). Median time to prostate-specific antigen (PSA) progression was not reached (NR) vs 6.5 months (HR, 0.32; 95% CI, 0.13-0.83; nominal P=0.0136), and median time to cytotoxic chemotherapy (TCC) was NR vs 16.9 months (HR, 0.09; 95% CI, 0.01-0.68; nominal P=0.0034). Median time to symptomatic progression (TSP) and OS were NR vs 28.9 months (HR, 0.39; 95% CI, 0.11-1.44; nominal P=0.1414) and NR vs 24.0 months (HR, 0.67; 95% CI, 0.27-1.71; nominal P=0.4027), respectively. In the HRR+ subgroup, any TEAE occurred in 100% vs 97.5% of patients, with grade ≥3 TEAEs in 74.1% vs 37.5%, serious adverse events (SAEs) in 55.6% vs 32.5%, and discontinuations in 25.9% vs 7.5%. Common TEAEs included anemia (40.7% vs 2.5%), hypertension (22.2% vs 5.0%), thrombocytopenia (14.8% vs 0%), hypokalemia (14.8% vs 7.5%), and neutropenia (11.1% vs 5.0%), while adverse events of special interest (AESIs) occurred in 85.2% vs 57.5% (grade ≥3: 73.9% vs 30.0%).
• AMPLITUDE is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter, global study evaluating the efficacy and safety of AKEEGA + prednisone plus androgen deprivation therapy (ADT) compared to matching oral placebo/abiraterone acetate in a dual action tablet formulation with prednisone + ADT in patients with deleterious germline or somatic HRR gene-altered metastatic castration-sensitive prostate cancer (mCSPC; N=696).^17-21
  • The primary endpoint of rPFS in the AKEEGA + prednisone group vs placebo/AAP group was met:^20,21
    • Median rPFS in the BRCA subgroup: not estimable (NE) vs 26.0 months; HR, 0.52; 95% CI, 0.37-0.72; P<0.0001.
    • Median rPFS in the HRR effector subgroup: NE vs 27.6 months; HR, 0.57; 95% CI, 0.42-0.77; P=0.0003.
    • Median rPFS in the intention-to-treat (ITT) population: NE vs 29.5 months; HR, 0.63; 95% CI, 0.49-0.80; P=0.0001.
  • A summary of AEs is described in Table: Adverse Events. The most common AEs of interest in the AKEEGA + prednisone group were anemia (AKEEGA + prednisone vs placebo/AAP, 51.6% vs 23.9%) and hypertension (43.8% vs 32.5%).^20,21
  • Pieczonka et al (2025)²² reported results from the phase 3 AMPLITUDE trial evaluating AKEEGA + prednisone in patients with HRR+ mCSPC (N=696). At a median follow-up of 30.8 months (55.6% with BRCA1/2 alterations), rPFS was NR with AKEEGA + prednisone vs 29.5 months (95% CI, 25.8-NR) with placebo + AAP (HR, 0.63; 95% CI, 0.49-0.80; P=0.0001), including in the prespecified BRCA1/2 subgroup (HR, 0.52; 95% CI, 0.37-0.72; P<0.0001). TSP was significantly improved (HR, 0.50; 95% CI, 0.36-0.69; P<0.0001), and OS at IA1 showed a trend favoring AKEEGA + prednisone (HR, 0.79; 95% CI, 0.59-1.04; P=0.10; BRCA1/2: HR, 0.75; 95% CI, 0.51-1.11; P=0.15). Grade 3/4 AEs occurred in 75% of patients in the AKEEGA + prednisone group vs 59% in the placebo + AAP group. TEAEs leading to treatment discontinuation were low (15% vs 10%, respectively).
  • Wang et al (2025)²³ presented a subgroup analysis of Chinese patients with BRCA1/2-mutated mCSPC from the AMPLITUDE trial (N=49). At a median follow-up of 30.8 months, rPFS (HR, 0.739; 95% CI, 0.28-1.98; P=0.5460), TSP (HR, 0.428; 95% CI, 0.107-1.713; P=0.2165), and time to subsequent therapy (TST; HR, 0.576; 95% CI, 0.199-1.667; P=0.3029) were reported for AKEEGA + prednisone vs placebo + AAP. OS at the interim analysis was (HR, 1.219; 95% CI, 0.343-4.325; P=0.7593). The safety profile was consistent with the overall study population, with no new safety signals observed.
• ProBio (Prostate-Biomarker, NCT03903835) is an ongoing, phase 3, outcome-adaptive, multiarm, multiple-assignment, randomized, open-label, international biomarker-driven platform study in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC) or L1 mCRPC. Patients will be randomized to receive either standard of care (SOC) or an experimental treatment including abiraterone acetate or AKEEGA, based on predefined biomarker signatures. The study has a planned enrollment of 750 patients. The efficacy and safety results have not been published.^24,25

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^4,6-8 and Efstathiou et al (2023)⁵ reported the efficacy and safety of AKEEGA + prednisone compared with placebo/AAP in mCRPC for patients with (n=423) and without (n=233) certain HRR gene mutations, including BRCA1/2 (n=225).

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, global study.
• Patients were prospectively allocated to cohort 1 or 2 based on prescreening for HRR+ or HRR- status. The HRR+ panel included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2 (qualified by plasma, tissue, and/or saliva/whole blood assays).^4,26
  • Patients in the HRR+ cohort were positive by ≥1 assay prior to randomization.
  • Patients in the HRR- cohort were tested by both tissue and plasma assays prior to randomization.
• A third, open-label cohort (cohort 3) was added to evaluate niraparib 200 mg and abiraterone acetate 1000 mg (dual action tablet formulation) orally (PO) once daily with prednisone 5 mg twice daily.
• Preplanned sensitivity analyses for OS included a proportional-hazards Cox regression multivariate analysis (MVA) adjusted for externally validated, clinically relevant baseline prognostic factors, inverse probability of censoring weighting (IPCW) adjusted for imbalances in the use of subsequent therapies, and censoring for death due to coronavirus disease 2019 (COVID-19).
• 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.⁴
• Select baseline patient characteristics are shown in Table: Select Baseline Patient Characteristics: BRCA1/2 and HRR+.

HRR+ Cohort

Efficacy

• A summary of results is provided in Table: Prespecified Primary and Key Secondary Endpoints.

IA2

• In the BRCA1/2 subgroup⁶:
  • The prespecified IPCW analysis of OS was used to account for imbalances in subsequent use of PARPi and other life-prolonging therapies: niraparib/AAP vs placebo/AAP (HR, 0.54; 95% CI, 0.33-0.90; nominal P=0.0181).
  • The prespecified OS MVA was used to account for important prognostic factors: niraparib/AAP vs placebo/AAP (HR, 0.68; 95% CI, 0.45-1.05; nominal P=0.0793).
  • These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
• In the HRR+ population⁶:
  • OS MVA was used to adjust for baseline characteristics: niraparib/AAP vs placebo/AAP (HR, 0.82; 95% CI, 0.60-1.10; nominal P=0.1821).
  • IPCW analysis was used to adjust for subsequent PARPi and other life-prolonging therapies: niraparib/AAP vs placebo/AAP (HR, 0.70; 95% CI, 0.49-0.99; nominal P=0.0414).
  • These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.

Final Analysis

• In the niraparib/AAP group and placebo/AAP group, 48 (22.6%) and 40 (19.0%) patients were still receiving treatment, respectively. There were 53.1% of patients in the niraparib/AAP vs 76.8% of patients in the placebo/AAP group that discontinued treatment due to disease progression.⁸
  • Results from the IPCW analysis revealed a longer OS with niraparib/AAP vs placebo/AAP in the HRR+ population (HR, 0.714; 95% CI, 0.525-0.970; nominal P=0.031) and in the BRCA1/2 subgroup (HR, 0.645; 95% CI, 0.415-1.002; nominal P=0.051). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  • At IA2, a prespecified sensitivity analysis in which COVID-19-related deaths were censored assessed the potential impact of the pandemic on OS. No COVID-19-related deaths occurred between IA2 and the final analysis. In the updated analysis with censoring of COVID-19-related deaths, the HR for OS was 0.871 (95% CI, 0.667-1.138; nominal P=0.310) in the HRR+ population and 0.704 (95% CI, 0.488-1.015; nominal P=0.059) in the BRCA1/2 subgroup. These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.

Safety

• At the final analysis,⁸ the safety profile in the BRCA+ subgroup was consistent with that of the HRR+ population and remained consistent with prior analyses. Safety data from the final analysis are summarized in Table: Safety Summary: Final Analysis (HRR+ Population).

TEAEs of special interest are presented in Table: TEAEs of Special Interest: Final Analysis (HRR+ Population).

• Safety profiles across IA1, IA2, and the final analysis were consistent, with no new safety signals.⁷

HRR- Cohort

Efficacy and Safety

• A prespecified futility analysis was conducted in the HRR- population after enrolling 233 of the planned 600 patients and approximately 125 composite progression events (first of rPFS, PSA progression, or death) occurred.^26,28
  • The composite progression endpoint (n=233) met futility criteria (HR, 1.09; 95% CI, 0.75-1.59, P=0.66), where futility was defined as ≥1.
  • A total of 83 PSA events (HR, 1.03; 95% CI, 0.67-1.59) and 65 rPFS events (HR, 1.03; 95% CI, 0.63-1.67) occurred.
• Additional grade 3/4 toxicity was observed in the niraparib/AAP group compared with the placebo/AAP group.²⁶
• Based on the efficacy and safety results in patients with HRR- mCRPC, the independent data monitoring committee recommended stopping enrollment in this cohort to support patient safety and prevent overtreatment.²⁶

Subgroup Analysis of the MAGNITUDE Trial

Ye et al (2026)¹⁶ evaluated the efficacy and safety of AKEEGA + prednisone in the Asian subgroup of HRR+ patients enrolled in the MAGNITUDE trial, with a focus on those with BRCA+ tumors.

Results

Patient Characteristics

• At the final data cutoff in May 2023, the analysis included 67 Asian patients with HRR+ mCRPC.
• Patients in this subgroup had lower prior exposure to chemotherapy and androgen receptor pathway inhibitors in mCSPC or non-metastatic CRPC/mHSPC and reduced prior use of AAP as first-line treatment for mCRPC. See Table: Demographic Characteristics and Disease Features of Patients with HRR+ mCRPC.

Efficacy

• At the final analysis, median follow-up among BRCA+ patients was 34.99 months overall, with 31.3 months in the AKEEGA + prednisone group and 37.0 months in the placebo + AAP group. See Table: Summary of Efficacy Outcomes in BRCA+ Subgroup.
• One patient (6.3%) in the AKEEGA + prednisone group and 11 patients (57.9%) in the placebo + AAP group received cytotoxic chemotherapy. From 18 to 30 months, 91.7% of patients in the AKEEGA + prednisone group remained chemotherapy-free, compared with 45.2% at 18 months and 38.8% at 24 and 30 months in the placebo + AAP group.
• In the AKEEGA + prednisone group, 80.8% of patients remained symptom-free through 30 months, whereas symptom-free rates declined in the placebo + AAP group to 73.7% at 12 months, 55.4% at 24 months, and 47.5% at 30 months.
• Survival rates were similar between groups until approximately 15 months, after which separation favored AKEEGA + prednisone, with 62.5% vs 47.4% of patients alive at 24 months and 54.7% vs 47.4% at 30 months.

Safety

• The frequency and severity of TEAEs in the HRR+ subgroup were comparable to those observed in the overall HRR+ population of the MAGNITUDE study, in which 74.0% of patients were White. See Table: Summary of TEAEs (Final Analysis) and Table: Summary of AESI (Final Analysis).
• Blood transfusions were received by 10 (14.9%) patients, all in the AKEEGA + prednisone group.
• Granulocyte colony-stimulating factor was administered to 3 (7.5%) patients in the placebo + AAP group and 1 (3.7%) patient in the AKEEGA + prednisone group.
• In the placebo + AAP group, cytopenias led to treatment interruptions in 8 (3.8%) patients due to anemia, 4 (1.9%) due to thrombocytopenia, and 3 (1.4%) due to neutropenia/leukopenia.
• In the AKEEGA + prednisone group, cytopenias led to treatment interruptions in 49 (23.1%) patients due to anemia, 24 (11.3%) due to thrombocytopenia, and 19 (9.0%) due to neutropenia/leukopenia.
• Treatment discontinuation occurred in 1 (0.5%) patient in the placebo + AAP group due to anemia, and in the AKEEGA + prednisone group in 6 (2.8%) patients due to anemia and 1 (0.5%) due to thrombocytopenia.
• Three patients in each group died within 30 days of the last dose. None of the deaths was considered related to study treatment by the investigators.

AMPLITUDE Study

Attard et al (2025)^20,21 reported efficacy and safety results of AKEEGA + prednisone + ADT vs placebo/AAP + ADT in patients with deleterious germline or somatic HRR gene-altered mCSPC (N=696).

Study Design/Methods

• This was a phase 3, randomized, double-blind, placebo-controlled, multicenter, global study.
• The study design is presented in Figure: AMPLITUDE Study Design.
• Key efficacy endpoint testing was conducted using a hierarchical graphical approach, first in the BRCA subgroup (BRCA1 or BRCA2 alterations), then HRR effector subgroup (i.e., immediate effectors of HRR at DNA double-strand breaks [BRCA subgroup+BRIP1, PALB2, RAD51B, RAD54L]), and then all ITT patients (HRR effector subgroup+CDK12, CHEK2, and FANCA).

Results

Patient Characteristics

• Patient characteristics were well balanced between the two groups, including BRCA and HRR effector subgroups (Table: Select Baseline Patient and Disease Characteristics). All patients received prior ADT via gonadotropin-releasing hormone (GnRH) agonist/antagonist GnRH or bilaterial orchiectomy.

Efficacy

• A summary of study results is provided in Table: Primary, Secondary, and Other Endpoint Results. The median follow-up was 30.8 months (data cutoff: January 7, 2025).
• Subgroup analyses by alteration type are summarized in Table: Subgroup Analysis by BRCA and non-BRCA Alterations.
• The treatment effect of AKEEGA + prednisone vs placebo/AAP on median rPFS in the ITT population was generally consistent across several prespecified subgroups, including patients with high-volume disease at baseline (41.2 months [events/N, 100/269] vs 26.3 months [130/271]; HR, 0.65; 95% CI, 0.50-0.85) and M1 disease at diagnosis (NE [100/301] vs 27.4 months [142/302]; HR, 0.60; 95% CI, 0.47-0.78).
• Although not a prespecified analysis, the HR for rPFS in patients without BRCA1/2 alterations was 0.81 (95% CI, 0.56-1.18).
• Of the 196 patients in the placebo/AAP group who discontinued treatment, 141 (72%) had received a life-prolonging subsequent treatment for prostate cancer at the data cutoff, selected according to the treating physician’s judgment and local approvals. Subsequent therapies used are provided in Table: Subsequent Therapy (ITT Population).
• Health-related quality of life (HRQoL) assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), improved from baseline at cycle 2 in the placebo + AAP group but initially declined at cycles 2-4 in the AKEEGA + prednisone group. Scores in the AKEEGA + prednisone group improved by cycle 5, with no differences between groups observed from cycles 5-37.

Safety

• A summary of AEs reported in both treatment arms from the time of first dose of the trial intervention through 30 days after the last dose is shown in Table: Adverse Events.
  • The most common AEs of interest in the AKEEGA + prednisone group were anemia (AKEEGA + prednisone vs placebo/AAP, 51.6% vs 23.9%) and hypertension (43.8% vs 32.5%), respectively.
  • Other common AEs of any grade included constipation (35.2% vs 16.4%), nausea (30.8% vs 14.4%), fatigue (26.2% vs 18.4%), arthralgia (21.0% vs 21.3%), back pain (19.6% vs 22.1%), COVID-19 (18.7% vs 20.4%), hot flush (18.2% vs 13.8%), leukopenia (16.7% vs 5.2%), vomiting (16.1% vs 8.6%), peripheral edema (15.9% vs 12.1%), weight decreased (15.3% vs 5.2%), and alanine aminotransferase increased (6.3% vs 15.5%) in the AKEEGA + prednisone vs placebo/AAP groups, respectively.

Pieczonka et al (2025)²² presented findings from the AMPLITUDE trial (NCT04497844), assessing the efficacy and safety of AKEEGA + prednisone in patients with HRR+ mCSPC, with a focus on the role of early genomic testing.

Study Design and Methods

• Eligible patients with ≥1 HRR gene alteration identified through central testing of tumor tissue or local tests, and those with ≤6 months of ADT with or without ≤6 cycles of docetaxel +/- ≤45 days of AAP, were randomized (1:1) to receive AKEEGA + prednisone or placebo + AAP.

Results

• A total of 696 patients (median age, 68 years) were randomized, including 55.6% with BRCA1/2 mutations, with a median follow-up of 30.8 months.
• The primary endpoint was achieved, with longer rPFS observed with AKEEGA + prednisone (median NR) compared with AAP (29.5 months [95% CI, 25.8-NR]; HR, 0.63; 95% CI, 0.49-0.80; P=0.0001), including in the prespecified BRCA1/2 subgroup (HR, 0.52; 95% CI, 0.37-0.72; P<0.0001).
• TSP was also improved with AKEEGA + prednisone (HR, 0.50; 95% CI, 0.36-0.69; P<0.0001; BRCA1/2: HR, 0.44; 95% CI, 0.29-0.68; P=0.0001).
• At the first interim analysis, OS showed a favorable trend (193/389 events) for AKEEGA + prednisone (HR, 0.79; 95% CI, 0.59-1.04; P=0.10; BRCA1/2: HR, 0.75; 95% CI, 0.51-1.11; P=0.15).
• Grade 3/4 AEs were reported in 75% of patients receiving AKEEGA + prednisone and 59% receiving AAP, with treatment discontinuations due to TEAEs in 15% and 10% of patients, respectively.

Subgroup Analysis of AMPLITUDE Trial

Wang et al (2025)²³ reported findings from the Chinese BRCA+ subgroup of the AMPLITUDE trial.

Study Design and Methods

• The analysis included patients with germline or somatic BRCA1/2 gene alterations from the AMPLITUDE trial who were randomized 1:1 to receive AKEEGA + prednisone or placebo + AAP, following ≤6 months of ADT, with or without ≤6 cycles of docetaxel and ≤45 days of AAP.

Results

• At the data cutoff of January 7, 2025, a total of 49 BRCA+ patients were included in the analysis (27 in the AKEEGA + prednisone group and 22 in the AAP group).
• At a median follow-up of 30.8 months, trends favored AKEEGA + prednisone for rPFS (HR, 0.739; 95% CI, 0.28-1.98; P=0.5460) with median NR in both the groups, TSP (HR, 0.428; 95% CI, 0.107-1.713; P=0.2165), and TST (HR, 0.576; 95% CI, 0.199-1.667; P=0.3029).
• OS data continues to mature (HR, 1.219; 95% CI, 0.343-4.325; P=0.7593) at IA1.
• The safety profile was consistent with the overall trial and East Asian populations, with no new safety signals reported.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 29 April 2026. Summarized in this response are relevant data pertaining to this topic in patients with prostate cancer.