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AKEEGA®

(niraparib and abiraterone acetate)

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AKEEGA® (niraparib and abiraterone acetate)

Medical Information

AKEEGA – Use of AKEEGA in Patients with BRCA Gene Mutations

Last Updated: 06/17/2025

Summary

  • MAGNITUDE (NCT03748641) is a phase 3, randomized, double-blind, placebocontrolled, global study that evaluated the efficacy and safety of AKEEGA with prednisone compared with placebo/abiraterone acetate with prednisone (AAP) as first-line 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).1-7
    • 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 for the BRCA1/2 subgroup are described in Table: Prespecified Primary and Key Secondary Endpoint Results: BRCA1/2 Subgroup.
    • At the first interim analysis (IA1)3:
      • In patients with BRCA1/2 mutations with 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 group compared to the placebo/AAP group: 16.6 months vs 10.9 months (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P=0.001).
    • At the final analysis6:
      • Across all BRCA1/2 patients, after a median follow-up of 37.3 months, 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).
    • Safety analyses were not specifically reported for patients with BRCA gene mutations. A summary of treatment-emergent adverse events (TEAEs) reported in both treatment arms is described in Table: Summary of Most Common (≥10% in Either Group) TEAEs at IA2 (HRR+ Population).
    • Results have been reported from a post hoc analysis that adjusted for imbalances in baseline characteristics using inverse probability of treatment weighting (IPTW) analysis (Table: Unadjusted and Adjusted Outcomes).8,9 
    • Results from an analysis of health-related quality of life (HRQoL), pain, and tolerability which evaluated Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory-Short Form (BPI-SF) score changes from baseline, have been reported.10,11
  • AMPLITUDE (NCT04497844) is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter, global study evaluating the efficacy and safety of AKEEGA with prednisone plus androgen deprivation therapy (ADT) compared to matching oral placebo/AAP plus ADT in patients with deleterious germline or somatic HRR gene-altered metastatic castration-sensitive prostate cancer (mCSPC), including BRCA1/2 (N=696).12-15
    • The primary endpoint of rPFS in the AKEEGA with prednisone group vs placebo/AAP group for the BRCAm subgroup was met: not estimable (NE) vs 26.0 months (HR, 0.52; 95% CI, 0.37-0.72; P<0.0001).
    • Safety analyses were not specifically reported for patients with BRCAm. A summary of TEAEs reported in both treatment arms is shown in Table: Adverse Events.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)3,5,6 and Efstathiou et al (2023)4 reported the efficacy and safety of AKEEGA with 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).
  • 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.

MAGNITUDE Study Design1-3,16-18

A screenshot of a computer screen AI-generated content may be incorrect.

Abbreviations: 1L, first-line; AA, abiraterone acetate; AAP, abiraterone acetate with prednisone; AML, acute myeloid leukemia; AR, androgen receptor; BM, biomarker; BPI-SF, Brief Pain Inventory-Short Form; CT, computed tomography; DAT, dual action tablet; ECOG PS, Eastern Cooperative Oncology Group performance status; EQ-5D-5L, European quality of life five-dimension five-level; FACT-P, functional assessment of cancer therapy-prostate; GnRHa, gonadotropin-releasing hormone analog; HRQoL, health-related quality of life; HRR, homologous recombination repair; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging; NIRA, niraparib; nmCRPC, nonmetastatic 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; PROs, patient-reported outcomes; PRO-CTCAE, PRO version of the common terminology criteria for adverse events; PSA, prostate-specific antigen; R, randomization; rPFS, radiographic progression-free survival; TCC, time to cytotoxic chemotherapy; TSP, time to symptomatic progression; TPSA, time to PSA progression.
aNovel second-generation AR-targeted therapy such as apalutamide, enzalutamide, or darolutamide; taxane-based chemotherapy; or >4 months of AAP before R.
bOpen-label cohort.
cPROs were collected to evaluate pain, prostate cancer symptoms, treatment-related tolerability, and overall HRQoL. Disease-related symptoms were assessed with the BPI-SF and FACT-P questionnaires. Treatment-related tolerability and experiences were assessed with select items from the PRO-CTCAE and a single item from the FACT-P regarding “side effect bother.” Overall HRQoL was to be measured with FACT-P and EQ-5D-5L.

Results

Patient Characteristics
  • Baseline characteristics were broadly comparable between treatment arms in the HRR+ cohort; 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
  • Select baseline patient characteristics in the BRCA1/2 subgroup are shown in Table: Select Baseline Patient Characteristics: BRCA1/2 Subgroup.

Select Baseline Patient Characteristics: BRCA1/2 Subgroup3,5,6 
NIRA/AAP
(n=113)
PBO/AAP
(n=112)
Median age, years (range)
67 (45-100)
68 (43-88)
Race, n (%)
   American Indian/Alaska native
0
0
   Asian
18 (15.9)
20 (17.9)
   Black/African American
3 (2.7)
0
   White
78 (69.0)
84 (75.0)
   Unknown
14 (12.4)
8 (7.1)
ECOG PS 0, n (%)
69 (61.1)
80 (71.4)
ECOG PS 1, n (%)
44 (38.9)
32 (28.6)
Bone metastases, n (%)
99 (87.6)
93 (83.0)
Visceral metastases, n (%)
26 (23.0)
22 (19.6)
   Liver
10 (8.8)
7 (6.3)
   Lung
12 (10.6)
11 (9.8)
Median PSA at study entry, µg/L (range)
18.7 (0.1-2225.8)
14.1 (0.1-4400.0)
Prior taxane-based chemotherapy for nmCRPC/mCSPC, n (%)
26 (23.0)
29 (25.9)
Prior ARPI for nmCRPC/mCSPC, n (%)
6 (5.3)
5 (4.5)
Prior AAP therapy for L1 mCRPC,a n (%)
30 (26.5)
29 (25.9)
Abbreviations: AAP, abiraterone acetate plus prednisone; ARPI, androgen receptor pathway inhibitor; ECOG PS, Eastern Cooperative Oncology Group performance status; L1, first-line; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; NIRA, niraparib; nmCRPC, nonmetastatic castration-resistant prostate cancer; PBO, placebo; PSA, prostate-specific antigen.
aPatients could have received up to 4 months of AAP before study entry.

BRCA1/2 Subgroup

Efficacy

Prespecified Primary and Key Secondary Endpoint Results: BRCA1/2 Subgroup3,5,7
NIRA/AAP
(n=113)
PBO/AAP
(n=112)
Hazard Ratio (95% CI)
P-Value
Primary Endpoint at IA1a
Median rPFS (BICR-assessed), months
16.6
10.9
0.53 (0.36-0.79)
0.001
Primary Endpoint at IA2b
Median rPFS (BICR-assessed), months
19.5
10.9
0.55 (0.39-0.78)
Nominal P=0.0007c
Key Secondary Endpoints at IA2
Median TCC, months
NR
27.3
0.56 (0.35-0.90)
Nominal P=0.0152c
Median TSP, months
NR
23.6
0.54 (0.35-0.85)
Nominal P=0.0071c
Median OS,d months
29.3
28.6
0.88 (0.58-1.34)
Nominal P=0.5505c
Key Secondary Endpoints at FAe
Median OS,f months
30.36
28.55
0.788 (0.554-1.120)
Nominal P=0.183c
OS with MVA
-
-
0.663 (0.464-0.947)
Nominal P=0.024c
Median TCC, months
NR
35.81
0.598 (0.387-0.924)
Nominal P=0.019c
Median TSP, months
-
-
0.562 (0.371-0.849)
Nominal P=0.006c
Abbreviations: AAP, abiraterone acetate with prednisone; BICR, blinded independent central review; CI, confidence interval; FA, final analysis; HRR, homologous recombination repair; IA1, first interim analysis; IA2, second interim analysis; MVA, multivariate analysis; NIRA, niraparib; NR, not reached; OS, overall survival; PBO, placebo; rPFS, radiographic progression-free survival; TCC, time to cytotoxic chemotherapy; TSP, time to symptomatic progression.
aMedian follow-up: 16.7 months.
bAs rPFS was found to be statistically significant at IA1, no formal statistical testing was performed for IA2 or FA. IA2 had an additional 8.1 months of follow-up from IA1.
cThese endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
dMedian follow-up: 24.8 months. There was a trend in stratified analysis toward improved OS with NIRA/AAP.
eMedian follow-up: 37.3 (range, 0.3-47.9) months. In the niraparib/AAP vs placebo/AAP group, median
treatment duration was 20.2 vs 15.2 months.
fFinal analysis occurred when 240/246 (97.6%) of the required number of events had accrued.
  • At the second interim analysis (IA2):
    • The prespecified IPCW analysis of OS was used to account for imbalances in subsequent use of PARP inhibitors 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.
  • At the final analysis7:
    • Results from the IPCW analysis revealed a longer OS with niraparib/AAP vs placebo/AAP 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 0.704 (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.
    • 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.
    • Subsequent treatment in patients with disease progression is summarized in Table: Subsequent Treatment (BRCA+ Subgroup).

Subsequent Treatment (BRCA+ Subgroup)7
Subsequent Treatment, n (%)
NIRA/AAP
(n=60)
PBO/AAP
(n=86)
Any subsequent therapy
42 (70.0)
74 (86.0)
PARP inhibitor
3 (5.0)a
29 (33.7)b
Chemotherapy
34 (56.7)
51 (59.3)
  Docetaxel
23 (38.3)
41 (47.7)
  Cabazitaxel
11 (18.3)
16 (18.6)
  Platinum-based chemotherapyc
9 (15.0)
8 (9.3)
   Other chemotherapyd
1 (1.7)
4 (4.7)
AR-targeted treatmente
12 (20.0)
24 (27.9)
Abbreviations: AAP, abiraterone acetate plus prednisone; ADP, adenosine diphosphate; AR, androgen receptor;   NIRA, niraparib; PARP, poly ADP-ribose polymerase; PBO, placebo.
aAll Olaparib.
bOlaparib, niraparib, rucaparib, or talazoparib.
cCisplatin, carboplatin, carboplatin + cabazitaxel or etoposide or docetaxel.
dEstramustine, etoposide, mitoxantrone, vinorelbine.
eEnzalutamide, darolutamide, apalutamide, abiraterone, or bicalutamide.
Safety
  • Safety analyses were not specifically reported for patients with BRCA gene mutations in the MAGNITUDE study.
  • At IA2, a total of 211 patients in the niraparib/AAP group and 203 patients in the placebo/AAP group reported AEs, described in Table: Summary of Most Common (≥10% in Either Group) TEAEs at IA2 (HRR+ Population).5
  • The most common AEs for niraparib/AAP vs placebo/AAP, regardless of causality, were anemia, hypertension, and constipation. The most common AEs leading to dose interruption or reduction in the niraparib/AAP group were anemia, thrombocytopenia, and neutropenia.5 

Summary of Most Common (≥10% in Either Group) TEAEs at IA2 (HRR+ Population)5
NIRA/AAP
(n=212)
PBO/AAP
(n=211)
Treatment-related AEs, n (%)
165 (77.8)
121 (57.3)
Treatment-related death, n
1a
1b
AEs leading to dose reduction of any agent, %
20.3
3.8
AEs leading to dose interruption of any agent, %
49.1
27.5
AEs leading to discontinuations of any agent, %
15.1
5.7
AEs leading to death, n (%)
19 (9.0)
9 (4.3)
   COVID-19 related, %
4.7
0.9
n (%)
NIRA/AAP
(n=212)
PBO/AAP
(n=211)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Patients with ≥1 SAE
93 (43.9)
-
-
61 (28.9)
-
-
Any TEAEs
211 (99.5)
121 (57.1)
32 (15.1)
203 (96.2)
91 (43.1)
13 (6.2)
Hematologic
      Anemia
106 (50.0)
61 (28.8)
3 (1.4)
48 (22.7)
18 (8.5)
0 (0.0)
      Thrombocytopenia
49 (23.1)
8 (3.8)
8 (3.8)
20 (9.5)
5 (2.4)
0 (0.0)
      Neutropenia
32 (15.1)
11 (5.2)
3 (1.4)
15 (7.1)
4 (1.9)
1 (0.5)
      Leukopenia
23 (10.8)
4 (1.9)
0 (0.0)
5 (2.4)
1 (0.5)
0 (0.0)
      Lymphopenia
22 (10.4)
8 (3.8)
1 (0.5)
4 (1.9)
1 (0.5)
1 (0.5)
   Cardiovascular
      Hypertension
70 (33.0)
33 (15.6)
0 (0.0)
47 (22.3)
26 (12.3)
0 (0.0)
      Hypokalemia
29 (13.7)
7 (3.3)
1 (0.5)
21 (10.0)
7 (3.3)
0 (0.0)
      Hyperglycemia
25 (11.8)
6 (2.8)
1 (0.5)
18 (8.5)
2 (0.9)
0 (0.0)
      Blood ALP increased
23 (10.8)
10 (4.7)
2 (0.9)
16 (7.6)
5 (2.4)
0 (0.0)
      ALT increased
11 (5.2)
0 (0.0)
0 (0.0)
22 (10.4)
10 (4.7)
0 (0.0)
   General disorders
      Fatigue
63 (29.7)
8 (3.8)
0 (0.0)
40 (19.0)
11 (5.2)
0 (0.0)
      Dyspnea
38 (17.9)
5 (2.4)
0 (0.0)
14 (6.6)
4 (1.9)
0 (0.0)
      Back pain
36 (17.0)
6 (2.8)
0 (0.0)
47 (22.3)
2 (0.9)
0 (0.0)
      Asthenia
35 (16.5)
2 (0.9)
1 (0.5)
21 (10.0)
1 (0.5)
0 (0.0)
      Arthralgia
32 (15.1)
1 (0.5)
0 (0.0)
23 (10.9)
2 (0.9)
0 (0.0)
      Dizziness
27 (12.7)
1 (0.5)
0 (0.0)
13 (6.2)
0 (0.0)
0 (0.0)
      Insomnia
24 (11.3)
0 (0.0)
0 (0.0)
8 (3.8)
0 (0.0)
0 (0.0)
      Bone pain
23 (10.8)
4 (1.9)
0 (0.0)
24 (11.4)
1 (0.5)
0 (0.0)
      Urinary tract infection
22 (10.4)
7 (3.3)
0 (0.0)
18 (8.5)
4 (1.9)
0 (0.0)
      Weight decreased
22 (10.4)
3 (1.4)
0 (0.0)
7 (3.3)
1 (0.5)
0 (0.0)
      Fall
16 (7.5)
2 (0.9)
0 (0.0)
29 (13.7)
6 (2.8)
0 (0.0)
   Gastrointestinal
      Constipation
70 (33.0)
1 (0.5)
0 (0.0)
33 (15.6)
0 (0.0)
0 (0.0)
      Nausea
52 (24.5)
1 (0.5)
0 (0.0)
31 (14.7)
1 (0.5)
0 (0.0)
      Decreased appetite
33 (15.6)
2 (0.9)
0 (0.0)
15 (7.1)
1 (0.5)
0 (0.0)
      Vomiting
31 (14.6)
2 (0.9)
0 (0.0)
16 (7.6)
2 (0.9)
0 (0.0)
Abbreviations: AAP, abiraterone acetate plus prednisone; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; COVID-19, coronavirus disease 2019; HRR, homologous recombination repair; IA2, second interim analysis; MI, myocardial infarction; NIRA, niraparib; PBO, placebo; SAE, severe adverse event; TEAE, treatment-emergent adverse event.
aDue to pneumonia.
bDue to acute MI.

Safety Summary: Final Analysis (HRR+ Population Cohort)6
AE, n (%)
NIRA/AAP (n=212)
PBO/AAP (n=211)
Any TEAEs
212 (100)
205 (97.2)
Related TEAEs
168 (79.2)
123 (58.3)
Grade 3-4 AEs
157 (74.1)
108 (51.2)
Serious AEs
100 (47.2)
65 (30.8)
   Related serious TEAEs
29 (13.7)
8 (3.8)
TEAEs leading to discontinuations of any agent
39 (18.4)
17 (8.1)
TEAEs leading to deatha
22 (10.4)
10 (4.7)
COVID-19 related or suspected TEAEs
10 (4.7)
2 (0.9)
AEs leading to dose interruption of NIRA/PBO
109 (51.4)
60 (28.4)
AEs leading to dose reduction of NIRA/PBO
43 (20.3)
8 (3.8)
AEs leading to discontinuations of NIRA/PBO
39 (18.4)
14 (6.6)
Abbreviations: AAP, abiraterone acetate plus prednisone; AE, adverse event; COVID-19, coronavirus disease 2019; HRR, homologous recombination repair; NIRA, niraparib; PBO, placebo; TEAE, treatment-emergent adverse event.Note: Median treatment exposure: 20.2 months in the NIRA/AAP group and 15.2 months in the PBO/AAP group.
aMost common were COVID-19 in the NIRA/AAP arm (2.8%) and suspected COVID-19, acute myocardial infarction, and myocardial infarction in the PBO/AAP arm (0.9% each).

TEAEs of Special Interest: Final Analysis (HRR+ Population)6
AE, n (%)
NIRA/AAP
(n=212)
PBO/AAP
(n=211)
Any Grade
Grade ≥3
Any Grade
Grade ≥3
Patients with ≥1 AE of special interest
179 (84.4)
113 (53.3)
136 (64.5)
64 (30.3)
   Anemia
111 (52.4)
65 (30.7)
48 (22.7)
18 (8.5)
   Hypertension
72 (34.0)
35 (16.5)
49 (23.2)
27 (12.8)
   Thrombocytopenia
51 (24.1)
18 (8.5)
20 (9.5)
5 (2.4)
   Fluid retention/edema
36 (17.0)
2 (0.9)
30 (14.2)
0
   Hypokalemia
34 (16.0)
12 (5.7)
22 (10.4)
7 (3.3)
   Neutropenia
34 (16.0)
14 (6.6)
15 (7.1)
5 (2.4)
   Hepatotoxicity
30 (14.2)
5 (2.4)
27 (12.8)
10 (4.7)
   Arrhythmia
28 (13.2)
7 (3.3)
16 (7.6)
4 (1.9)
   Ischemic heart disease
11 (5.2)
8 (3.8)
10 (4.7)
8 (3.8)
   Cerebrovascular disorders
7 (3.3)
2 (0.9)
5 (2.4)
2 (0.9)
   Cardiac failure
6 (2.8)
4 (1.9)
4 (1.9)
1 (0.5)
   Osteoporosis including
   osteoporosis-related fractures
3 (1.4)
0
6 (2.8)
0
   Acute myeloid leukemia
0
0
1 (0.5)
1 (0.5)
   Rhabdomyolysis/myopathy
0
0
1 (0.5)
0
Abbreviations: AAP, abiraterone acetate plus prednisone; AE, adverse event; HRR, homologous recombination repair; NIRA, niraparib; PBO, placebo; TEAE, treatment-emergent adverse event.
  • Safety profiles across IA1, IA2, and the final analysis were consistent, with no new safety signals.7 

Post Hoc Analysis

Roubaud et al (2024)8,9 reported the efficacy of AKEEGA with AAP in patients with BRCA1/2-altered mCRPC (n=225) in MAGNITUDE after adjustment for imbalances in baseline characteristics. In a post hoc analysis that adjusted for imbalances in baseline characteristics using IPTW analysis, time-to-event outcome analyses were evaluated in patients with BRCA1/2-altered mCRPC. MVA was conducted based on prespecified prognostic variables of OS in mCRPC. Outcomes are described in Table: Unadjusted and Adjusted Outcomes.


Unadjusted and Adjusted Outcomes8,9
NIRA/AAP (n=113)
PBO/AAP (n=112)
Hazard Ratio (95% CI)
P-Value
rPFS, months
    Unadjusted, median (95% CI)
19.5 (15.0-28.7)
10.9 (8.3-13.7)
0.55 (0.39-0.78)
0.183
    IPTW, median (95% CI)
22.0 (16.5-28.7)
8.4 (8.2-12.7)
0.47 (0.33-0.66)
<0.001
    Multivariate analysis
-
-
0.50 (0.35-0.70)
<0.001
TCC, months
    Unadjusted, median (95% CI)
NE (31.4-NE)
28.2 (20.7-NE)
0.60 (0.39-0.92)
0.0192
    IPTW, median (95% CI)
NE (NE-NE)
25.0 (17.9-NE)
0.49 (0.32-0.76)
0.0012
    Multivariate analysis
-
-
0.48 (0.31-0.75)
0.0014
TSP, months
    Unadjusted, median (95% CI)
NE (36.2-NE)
21.7 (17.6-35.8)
0.56 (0.37-0.85)
0.0056
    IPTW, median (95% CI)
NE (36.2-NE)
21.3 (17.3-35.8)
0.49 (0.33-0.74)
0.0007
    Multivariate analysis
-
-
0.51 (0.33-0.78)
0.0017
OS, months
   Unadjusted, median (95% CI)
30.4 (27.6-NE)
28.6 (23.8-33.0)
0.79 (0.55-1.12)
0.183b
     IPTW, median (95% CI)
34.1 (28.5-NE)
27.4 (20.8-32.4)
0.65 (0.46-0.93)
0.017
     Multivariate analysis
-
-
0.66 (0.46-0.95)
0.024b
Time to PSA progression, months
     Unadjusted, median (95% CI)
20.7 (14.8-NE)
9.2 (7.4-14.7)
0.51 (0.35-0.73)
0.0002
     IPTW, median (95% CI)
22.1 (16.8-NE)
8.3 (6.5-12.9)
0.42 (0.30-0.60)
<0.0001
     Multivariate analysis
-
-
0.37 (0.25-0.53)
<0.0001
Time to treatment discontinuation, months
    Unadjusted, median (95% CI)
20.5 (16.6-22.3)
14.4 (11.3-16.6)
0.67 (0.50-0.90)
0.008
    IPTW, median (95% CI)
20.9 (16.9-23.8)
14.0 (11.0-15.9)
0.56 (0.41-0.75)
<0.001
    Multivariate analysis
-
-
0.57 (0.42-0.77)
<0.001
PFS2, months
    Unadjusted, median (95% CI)
28.7 (25.2-34.1)
23.8 (19.5-28.6)
0.72 (0.51-1.02)
0.0606
    IPTW, median (95% CI)
29.5 (27.0-NE)
22.9 (18.0-25.7)
0.58 (0.41-0.82)
0.002
    Multivariate analysis
-
-
0.64 (0.45-0.90)
0.0116
Abbreviations: AAP, abiraterone acetate plus prednisone; CI, confidence interval; IPTW, inverse probability of  treatment weighting; NE, not estimable; NIRA, niraparib; OS, overall survival; PBO, placebo; PFS2, second   progression-free survival; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival; TCC, time  to cytotoxic chemotherapy; TSP, time to symptomatic progression.
arPFS is reported using data from the second interim analysis of MAGNITUDE, and remaining outcomes are  reported using data from the final analysis.
bThese endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and  statistical significance has not been established. Note: Unadjusted hazard ratios were calculated using a stratified model, with prior AAP and prior taxane-based  chemotherapy as stratification factors.

AMPLITUDE Study

Attard et al (2025)15 reported efficacy and safety results of AKEEGA with prednisone plus ADT vs placebo/AAP plus ADT in patients with deleterious germline or somatic HRR gene-altered mCSPC (N=696), including BRCAm (n=387).

Study Design/Methods

  • Phase 3, randomized, double-blind, placebo-controlled, multicenter, global study
  • The study design is presented in Figure: AMPLITUDE Study Design.
  • The HRR effectors group (BRCA1/2 + BRIP1, PALB2, RAD51B, RAD54L) are prespecified for formal statistical analysis after BRCAm and prior to HRRm.
    • BRCA1/2 alterations include co-occurring BRCA1 or BRCA2 alterations.

AMPLITUDE Study Design12-15

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Abbreviations: AA, abiraterone acetate; AAP, abiraterone acetate plus prednisone; ADT, androgen deprivation therapy; AML, acute myeloid leukemia; ARPI, androgen receptor pathway inhibitor; BRCA, breast cancer susceptibility gene; CT, computed tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; HRR, homologous recombination repair; mCSPC, metastatic castration-sensitive prostate cancer; MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging; NIRA, niraparib; PARPi, poly (adenosine diphosphate-ribose) polymerase inhibitor; PBO, placebo; PC, prostate cancer; QD, once daily; R, randomization; rPFS, radiographic progression-free survival.
aPatients with lymph node-only disease were not eligible. Metastatic disease as documented by CT, MRI, or bone scan.
bFinal dose must be received ≤3 months prior to randomization.
c≤1 course radiation or surgery for symptoms; radiation completed before randomization.
dIf completed ≥1 year before randomization.
eIncluding radiation, prostatectomy, lymph node dissection, and systemic therapies.
fBy investigator. Defined as time from randomization to date of radiographic progression or death, whichever occurred first.
gEvaluation based on adverse events and clinical lab evaluations using National Cancer Institute Common Terminology Criteria for Adverse
Events v5.0.

Results

Patient Characteristics

Select Baseline Patient and Disease Characteristics: HRRm (ITT) Population15 
AKEEGA + Prednisone Group
(N=348)
PBO/AAP Group
(N=348)
Median age, years (range)
68 (40–88)
67 (40-92)
Median PSA at initial diagnosis, ng/mL (range)
112 (0.1-17475)a
102 (0.1-15900)b
ECOG-PS score, n (%)
   0
242 (70)
218 (63)
   ≥1
106 (30)
130 (37)
Gleason score at initial diagnosis, n (%)
   >8
276 (79)
262 (75)
Metastatic stage at initial diagnosis, n (%)
   M1 (synchronous)
301 (86)
302 (87)
Disease volume, n (%)
   High
269 (77)
271 (78)
Prior docetaxel use in mCSPC, n (%)
54 (16)
56 (16)
Site of metastases,d n (%)
   Bone only
146 (42)
154 (44)c
   Visceral
57 (16)
54 (16)c
   Lymph nodes
173 (50)
161 (46)c
BRCA alteration, n (%)
191 (55)
196 (56)c
Abbreviations: AAP, abiraterone acetate plus prednisone; ECOG PS, Eastern Cooperative Oncology Group performance status; HRR, homologous recombination repair; ITT, intention to treat; mCSPC, metastatic castration-sensitive prostate cancer; PBO, placebo; PSA, prostate-specific antigen.
an=258; bn=275; cn=347.
dNon-mutually exclusive.
Efficacy

Primary and Secondary Endpoint Results: BRCAma Subgroup15 
AKEEGA + Prednisone Group
(n=191)
PBO/AAP Group (n=196)
HR (95% CI);
P-value
Events/N
AKEEGA + Prednisone Group
PBO/AAP Group
Primary Endpoint
Median rPFS,b months
NE
26.0
0.52 (0.37-0.72); <0.0001
57/191
93/196
Secondary Endpoints
Median TSP,c months
NE
NE
0.44 (0.29-0.68); 0.0001
31/191
66/196
Median OS,c,d months
NE
NE
0.75 (0.51-1.11); 0.15
44/191
61/196
Abbreviations: AAP, abiraterone acetate plus prednisone; CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival; PBO, placebo; rPFS, radiographic progression-free survival; TSP, time to symptomatic progression.
aSingle or co-occurring BRCA1 or BRCA2 alterations.
bBy investigator review. The results by blinded independent central review were similar: HR, 0.51 (95% CI, 0.37-0.72). This is the first and final analysis.
cFirst interim analysis.
dConducted when 193 patients died (n=85 in AKEEGA group and n=108 in PBO/AAP group), which is ~50% of total needed events.
Safety
  • Safety analyses were not specifically reported for patients with BRCAm in the AMPLITUDE study.
  • A summary of AEs reported in both treatment arms is shown in Table: Adverse Events. Other common AEs of any grade included constipation (35% vs 16%), nausea (31% vs 14%), fatigue (26% vs 18%), and arthralgia (21% each), in the AKEEGA vs placebo/AAP groups, respectively.

Adverse Events15 
AE, n (%)
AKEEGA + Prednisone Groupa
(n=347)c
PBO/AAP Groupb
(n=348)
Any Grade
Grade 3-4
Any Grade
Grade 3-4
Any TEAE
346 (>99)
261 (75)
341 (98)
205 (59)
Treatment-related TEAEsd
309 (89)
193 (56)
257 (74)
105 (30)
Serious AEs
136 (39)
-
96 (28)
-
Treatment-related serious AEs
44 (13)
-
11 (3)
-
TEAEs leading to treatment discontinuatione
51 (15)f
-
36 (10)
-
TEAEs leading to dose reduction
76 (22)
-
24 (7)
-
TEAEs leading to deathg
14 (4)
-
7 (2)
-
TEAEs of interesth
Patients with ≥1 AE of interest
306 (88)
217 (63)
261 (75)
132 (38)
Hematologic
   Anemia
179 (52)
101 (29)
83 (24)
16 (5)
   Neutropenia
76 (22)
33 (10)
28 (8)
7 (2)
   Thrombocytopenia
66 (19)
24 (7)
20 (6)
1 (<1)
   MDS
1 (<1)
1 (<1)
0
0
Cardiovascular
   Hypertension
155 (45)
93 (27)
113 (33)
64 (18)
   Arrhythmia
68 (20)
19 (5)
28 (8)
11 (3)
   Cardiac failure
20 (6)
9 (3)
6 (2)
4 (1)
Others
   Hypokalemia
92 (27)
40 (12)
70 (20)
38 (11)
   Hepatotoxicity
46 (13)
8 (2)
71 (20)
19 (5)
Abbreviations: AAP, abiraterone acetate plus prednisone; AE, adverse event; COVID-19, coronavirus 2019; MDS, myelodysplastic syndrome; NIRA, niraparib; PBO, placebo; TEAE, treatment-emergent adverse event.
aMedian treatment duration: 25.3 months.
bMedian treatment duration: 22.5 months.
cOne randomized patient never received study drug.
dPer assessment by investigator.
eAn AE was counted as leading to discontinuation of study treatment if it led to withdrawal of NIRA/PBO or AA/PBO or prednisone.
fIncluded one case of MDS.
gIncluded 4 cases of respiratory infection, including 2 attributed as related to COVID-19, 4 attributed to cardiac causes, 3 classified as sudden death, and 1 each of sepsis, subdural hematoma, and multiorgan dysfunction syndrome.
hPatients were counted only once for any given event, regardless of the number of times they actually experienced the event. The event experienced by the patient with the worst toxicity grade was used. If a patient had missing toxicity for a specific AE, the patient was only counted in the total column for the AE.

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 26 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.

 

References

Show
1 Janssen Research & Development, LLC. A study of niraparib in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone for treatment of participants with metastatic prostate cancer (MAGNITUDE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 June 11]. Available from: https://clinicaltrials.gov/show/NCT03748641 NLM Identifier: NCT03748641.  
2 Chi KN, Rathkopf D, Attard G. A phase 3 randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (MAGNITUDE). Poster presented at: American Society of Clinical Oncology (ASCO) Scientific Program; May 29-31, 2020; Virtual.  
3 Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339-3351.  
4 Efstathiou E, Smith M, Sandhu S, et al. Niraparib with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of MAGNITUDE. Poster presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium; February 16-18, 2023; San Francisco, CA.  
5 Chi KN, Sandhu S, Smith MR, et al. Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial. Ann Oncol. 2023;34(9):772-782.  
6 Chi KN, Castro E, Attard G, et al. Niraparib and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: final overall survival analysis for the phase 3 MAGNITUDE trial. [published online ahead of print May 05, 2025]. Eur Urol Oncol. doi:10.1016/j.euo.2025.04.012.  
7 Chi KN, Castro E, Attard G, et al. Niraparib (NIRA) with abiraterone acetate plus prednisone (AAP) as first-line (1L) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations: three-year update and final analysis of MAGNITUDE. Oral Presentation presented at: European Society of Medical Oncology (ESMO) Congress; October 20-24, 2023; Madrid, Spain.  
8 Roubaud G, Attard G, Boegemann M, et al. Adjustment for imbalances in baseline characteristics in the MAGNITUDE phase 3 study confirms the clinical benefit of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic prostate cancer. Eur J Cancer. 2024;209:114183.  
9 Roubaud G, Attard G, Boegemann M, et al. Supplement to: Adjustment for imbalances in baseline characteristics in the MAGNITUDE phase 3 study confirms the clinical benefit of niraparib in combination with abiraterone acetate plus prednisone in patients with metastatic prostate cancer. Eur J Cancer. 2024;209:114183.  
10 Rathkopf D, Roubaud G, Chi KN, et al. Health-related quality of life and pain in the MAGNITUDE study of niraparib with abiraterone acetate and prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL and Virtual.  
11 Rathkopf DE, Roubaud G, Chi KN, et al. Patient-reported outcomes for patients with metastatic castration-resistant prostate cancer and BRCA1/2 gene alterations: final analysis from the randomized phase 3 MAGNITUDE trial. Eur Urol. 2024;S0302-2838(24)02594-6.  
12 Rathkopf DE, Chi KN, Olmos D, et al. AMPLITUDE: a study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombinant repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC). Rapid abstract presentation presented at: American Society of Clinical Oncology Genitourinary (ASCO) Genitourinary Cancers Symposium; February 11-13, 2021; Virtual.  
13 Janssen Research & Development, LLC. A study of niraparib in combination with abiraterone acetate and prednisone versus abiraterone acetate and prednisone for the treatment of participants with deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-sensitive prostate cancer (mCSPC) (AMPLITUDE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 June 11]. Available from: https://clinicaltrials.gov/show/NCT04497844 NLM Identifier: NCT04497844.  
14 Rathkopf DE, Chi KN, Olmos D, et al. AMPLITUDE: niraparib and abiraterone acetate plus prednisone to treat patients with metastatic castration-sensitive prostate cancer and deleterious germline or somatic homologous recombination repair gene alterations. Poster presented at: 23rd Annual Meeting of the Society of Urologic Oncology (SUO); November 30-December 2, 2022; San Diego, CA.  
15 Attard G, Agarwal N, Graff JN, et al. Phase 3 AMPLITUDE trial: niraparib and abiraterone acetate plus prednisone for metastatic castration-sensitive prostate cancer patients with alterations in homologous recombination repair genes. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2025; Chicago, IL.  
16 Chi KN, Rathkopf DE, Smith MR, et al. Phase 3 MAGNITUDE study: first results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. Oral Presentation presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, CA.  
17 Chi KN, Rathkopf D, Smith MR, et al. Protocol for: Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339-3351.  
18 Chi KN, Rathkopf D, Smith MR. Supplement to: Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339-3351.  
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