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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

AKEEGA® (niraparib and abiraterone acetate)

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Use of AKEEGA in Patients with BRCA Gene Mutations

Last Updated: 10/10/2024

Summary

MAGNITUDE (NCT03748641) is a phase 3, randomized, double-blind, placebocontrolled, global 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. The primary endpoint is radiographic progression-free survival (rPFS). Key secondary endpoints include time to cytotoxic chemotherapy (TCC), time to symptomatic progression (TSP), and overall survival (OS).¹^-⁶
- 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.
- At the first interim analysis⁴:
  - 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/abiraterone acetate with prednisone (AAP) group compared to the placebo/AAP group: 16.6 months vs 10.9 months (HR, 0.53; 95% CI, 0.36-0.79; P=0.001).
- At the second interim analysis⁶:
  - In patients with BRCA1/2 mutations after 8.1 months of additional follow-up from the first interim analysis, a consistent treatment effect in BICR-assessed median rPFS was observed in the niraparib/AAP group compared with the placebo/AAP group: 19.5 months vs 10.9 months (HR, 0.55; 95% CI, 0.39 0.78; nominal P=0.0007). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  - In patients with BRCA1/2 mutations, an improvement in TCC (HR, 0.56; 95% CI, 0.350.90; nominal P=0.0152) and TSP (HR, 0.54; 95% CI, 0.35-0.85; nominal P=0.0071) was observed in the niraparib/AAP group compared with the placebo/AAP group.⁵ These endpoints were not adjusted for multiple comparisons. Therefore, the Pvalues displayed are nominal, and statistical significance has not been established.
  - With a median follow-up of 24.8 months in the BRCA1/2 subgroup, there was a trend toward improved OS in the niraparib/AAP group compared to the placebo/AAP group in the stratified analysis: 29.3 months vs 28.6 months (HR, 0.88; 95% Cl, 0.58-1.34; nominal P=0.5505). 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:
  - Across all BRCA1/2 patients, after a median follow-up of 35.9 months, median OS favored the niraparib/AAP group compared to the placebo/AAP group:
  - 30.4 months vs 28.6 months (HR 0.788; 95% CI, 0.554-1.120; nominal P=0.1828). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  - OS benefit in the niraparib/AAP group was also demonstrated in a preplanned multivariate analysis using prespecified prognostic factors (HR 0.663; 95% CI, 0.464-0.947; nominal P=0.0237). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
- A summary of efficacy results for the BRCA1/2 subgroup is provided in Table: Prespecified Primary and Key Secondary Endpoint Results: BRCA1/2 Subgroup.
- Safety analyses were not specifically reported for patients with BRCA gene mutations in the MAGNITUDE study.
- A summary of treatment-emergent adverse events (TEAEs) is described in Table: Summary of Most Common (≥10% in Either Group) TEAEs. Grade ≥3 adverse events (AEs) were reported in 153 (72.2%) and 104 (49.3%) patients in the niraparib/AAP and in the placebo/AAP group, respectively. Discontinuation of niraparib or placebo due to a TEAE occurred in 15.1% of patients in the niraparib/AAP group and 5.7% of patients in the placebo/AAP group.⁶ Safety profiles at the final analysis⁷ and second interim analysis⁵ were consistent with that of the first interim analysis, with no new safety signals observed.⁵
- Results from an analysis of health-related quality of life (HRQoL) and pain, 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.⁸

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)⁴^,⁶^,⁷ and Efstathiou et al (2023)⁵ 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 orally (PO) once daily or matching placebo in combination with abiraterone acetate 1000 mg PO once daily with prednisone 5 mg twice daily.

The study design is presented in Figure: MAGNITUDE Study Design.

MAGNITUDE Study Design¹^,²^,⁴

Abbreviations: AA, abiraterone acetate; AML, acute myeloid leukemia; AR, androgen receptor; BPI-SF, Brief Pain Inventory-Short Form; CT, computed tomography; DAT, dual action tablet; 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.

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.⁴
Select baseline patient characteristics in the BRCA+ population are shown in Table: Select Baseline Patient Characteristics: BRCA+ Population.

Select Baseline Patient Characteristics: BRCA+ Population⁶

	NIRA/AAP (n=113)	PBO/AAP (n=112)
Median age, years (range)	67 (45-100)	68 (43-88)
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 mCSPC, n (%)	26 (23.0)	29 (25.9)
Prior AR-targeted therapy 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; AR, androgen receptor; 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, non-metastatic 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

A summary of results for the BRCA1/2 subgroup is provided in Table: Prespecified Primary and Key Secondary Endpoint Results: BRCA1/2 Subgroup.
At the first interim analysis⁴:
- In patients with BRCA1/2 mutations at a median follow-up of 16.7 months, a statistically significant improvement in BICR-assessed median rPFS was observed in the niraparib/AAP group compared to the placebo/AAP group: 16.6 months vs 10.9 months (HR, 0.53; 95% CI, 0.36-0.79; P=0.001).
At the second interim analysis, at 8.1 months of additional follow-up from the first interim analysis, the following endpoints were evaluated.⁵^,⁶ These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
- In patients with BRCA1/2 mutations, a consistent treatment effect in BICR-assessed median rPFS was observed in the niraparib/AAP group compared with the placebo/AAP group: 19.5 months vs 10.9 months (HR, 0.55; 95% CI, 0.39-0.78; nominal P=0.0007).
- In patients with BRCA1/2 mutations, an improvement in TCC (HR, 0.56; 95% CI, 0.350.90; nominal P=0.0152) and TSP (HR, 0.54; 95% CI, 0.35-0.85; nominal P=0.0071) was observed in the niraparib/AAP group compared with the placebo/AAP group.
- At a median follow-up of 24.8 months in the BRCA1/2 subgroup, there was a trend toward improved OS in the niraparib/AAP group compared to the placebo/AAP group in the stratified analysis: 29.3 months vs 28.6 months (HR, 0.88; 95% Cl,0.58-1.34; nominal P=0.5505).
  - After adjusting for important prognostic factors in a multivariate analysis and accounting for differences in subsequent therapies in an inverse probability censoring weighted (IPCW) analysis, OS improvement was observed with niraparib/AAP compared with placebo/AAP in the BRCA1/2 population (HR, 0.68; 95% CI, 0.451.05; nominal P=0.0793 and HR, 0.54; 95% CI, 0.33-0.90; nominal P=0.0181, respectively).
At the final analysis⁷:
- After a median follow-up of 35.9 months, median OS favored the niraparib/AAP group compared to the placebo/AAP group: 30.4 months vs 28.6 months (HR 0.788; 95% CI, 0.554-1.120; nominal P=0.1828). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  - Median treatment duration was 20.5 months for the niraparib/AAP group and 14.4 months for the placebo/AAP group.
  - In the niraparib/AAP group, 53.1% patients discontinued treatment due to disease progression compared with 76.8% in the placebo/AAP group. Use of subsequent treatment was high and included the use of PARP inhibitors and platinum-based chemotherapy.

Prespecified Primary and Key Secondary Endpoint Results: BRCA1/2 Subgroup⁴^,⁶^,⁷

	NIRA/AAP (n=113)	PBO/AAP (n=112)	Hazard Ratio (95% CI)	P-Value
Primary Endpoint at IA1
Median rPFS (BICR-assessed), months	16.6	10.9	0.53 (0.36-0.79)	0.001
Primary Endpoint at IA2^a
Median rPFS (BICR-assessed), months	19.5	10.9	0.55 (0.39-0.78)	Nominal P=0.0007^b
Key Secondary Endpoints at IA2
Median TCC, months	NR	27.3	0.56 (0.35-0.90)	Nominal P=0.0152^b
Median TSP, months	NR	23.6	0.54 (0.35-0.85)	Nominal P=0.0071^b
Median OS, months	29.3	28.6	0.88(0.58-1.34)	Nominal P=0.5505^b
Key Secondary Endpoints at FA
Median OS, months	30.4	28.6	0.788 (0.554-1.120)	Nominal P=0.1828^b
OS with MVA	-	-	0.663 (0.464-0.947)	Nominal P=0.0237^b
Median TCC, months	-	-	0.598 (0.387-0.924)	Nominal P=0.0192^b
Median TSP, months	-	-	0.562(0.371-0.849)	Nominal P=0.0056^b
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; NIRA, niraparib; NR, not reached; OS, overall survival; PBO, placebo; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival; TCC, time to cytotoxic chemotherapy; TSP, time to symptomatic progression.^aAs rPFS was found to be statistically significant at IA1, no formal statistical testing was performed for IA2.^bThese endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.

Safety

Safety analyses were not specifically reported for patients with BRCA gene mutations in the MAGNITUDE study.
At the second interim analysis⁶:
- 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.
- Grade ≥3 AEs were reported in 153 (72.2%) and 104 (49.3%) patients in the niraparib/AAP and placebo/AAP groups, respectively.
- Treatment-related AEs were reported in 165 (77.8%) and 121 (57.3%) patients in the niraparib/AAP and placebo/AAP groups, respectively.
  - There was 1 treatment-related death in each group (niraparib/AAP: pneumonia; placebo/AAP: acute myocardial infarction).
- Serious AEs occurred in 93 (43.9%) patients in the niraparib/AAP group and 61 (28.9%) patients in the placebo/AAP group.
- Dose reduction of niraparib or placebo due to an AE occurred in 20.3% of patients in the niraparib/AAP group vs 3.8% of patients in the placebo/AAP group.
  - The most common AEs leading to dose interruption or reduction in the niraparib/AAP group were anemia, thrombocytopenia, and neutropenia.
- Discontinuation of niraparib or placebo due to an AE occurred in 15.1% of patients in the niraparib/AAP group and 5.7% of patients in the placebo/AAP group.
- Death due to an AE occurred in 19 (9.0%) patients in the niraparib/AAP group and 9 (4.3%) patients in placebo/AAP group.
  - Coronavirus disease-2019 (COVID-19) was the leading cause of death in the niraparib/AAP group (4.7%) and in the placebo/AAP group (0.9%).
- Safety profiles across both interim analyses were consistent, with no new safety signals. The most common AEs for niraparib/AAP vs placebo/AAP, regardless of causality, were anemia (50.0% vs 22.7%, respectively), hypertension (33.0% vs 22.3%, respectively), and constipation (33.0% vs 15.6%).
At the final analysis⁷:
- The safety profile in the BRCA+ population was consistent with that of the HRR+ cohort and remained consistent with prior analyses. Pulmonary embolism occurred in 4.7% and 1.4% of patients in the niraparib/AAP and placebo/AAP groups, respectively, with no cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in the niraparib/AAP arm.
- Grade 3-4 AEs were reported in 157 (74.1%) and 108 (51.2%) patients in the niraparib/AAP and placebo/AAP groups, respectively.
- Serious AEs occurred in 100 (47.2%) patients in the niraparib/AAP group and 65 (30.8%) patients in the placebo/AAP group.
- In the niraparib/AAP group, 18.4% patients discontinued treatment due to TEAEs compared with 8.1% in the placebo/AAP group.
- Death due to TEAEs occurred in 22 (10.4%) patients in the niraparib/AAP group and 10 (4.7%) patients in the placebo/AAP group.
  - COVID-19 related or suspected was the leading cause of death in the niraparib/AAP group (4.7%) and in the placebo/AAP group (0.9%).
- Dose interruption of niraparib or placebo due to an AE occurred in 51.4% of patients in the niraparib/AAP group vs 28.4% of patients in the placebo/AAP group.
- Dose reduction of niraparib or placebo due to an AE occurred in 20.3% of patients in the niraparib/AAP group vs 3.8% of patients in the placebo/AAP group.
- Discontinuation of niraparib or placebo due to an AE occurred in 18.4% of patients in the niraparib/AAP group and 6.6% of patients in the placebo/AAP group.
Safety profiles across both interim analyses⁶ and the final analysis⁷ were consistent, with no new safety signals.

Summary of Most Common (≥10% in Either Group) TEAEs⁶

n (%)	NIRA/AAP (n=212)			PBO/AAP (n=211)
n (%)	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)
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 with prednisone; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; PBO, placebo; SAE, severe adverse event; TEAE, treatment-emergent adverse event.

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

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 2024 September 20]. 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 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.
4	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.
5	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.
6	Chi K, Sandhu S, Smith M, 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.
7	Chi K, 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 (FA) of MAGNITUDE. Oral presentation presented at: European Society of Medical Oncology (ESMO) Congress; October 20-24, 2023; Madrid, Spain.
8	Rathkopf DE, Roubaud G, Chi KN, et al. Patient-reported outcomes (PRO) in patients (pts) with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC) receiving niraparib (NIRA) with abiraterone acetate and prednisone (AAP): results from final analysis of the MAGNITUDE study. Poster presented at: American Society of Clinical Oncology Genitourinary (ASCO-GU) Cancers Symposium; January 25, 2024; San Francisco, CA.