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 (L1) therapy in metastatic castration-resistant prostate cancer (mCRPC) for patients with certain homologous recombination repair (HRR) mutations, including BRCA1/2. Patients were stratified by prior androgen receptor targeted (ART) therapy for nonmetastatic castration-resistant prostate cancer (nmCRPC)/metastatic castrationsensitive prostate cancer (mCSPC; ie, enzalutamide, apalutamide, or darolutamide) and prior AAP therapy for L1 mCRPC.^1-7
  • Of 225 total patients enrolled with BRCA1/2 mutations, 6 (5.3%) in the niraparib/AAP group and 5 (4.3%) in placebo/AAP group received prior ART therapy for nmCRPC or mCSPC.⁵
  • Efficacy and safety analyses were not specifically reported for patients who received prior ART therapy in the MAGNITUDE study.
  • Prespecified primary and key secondary endpoint results for the BRCA1/2 population are described in Table: Prespecified Primary and Key Secondary Endpoints in the BRCA1/2 Population.
  • At the second interim analysis^2,5:
    • BRCA1/2 patients who received AAP run-in treatment for ≤2 months had a treatment benefit similar to that in patients who did not receive prior AAP. BRCA1/2 patients who received AAP run-in treatment for >2-4 months did not show a radiographic progression-free survival (rPFS) benefit.⁸ Outcomes are shown in Table: Impact of AAP Run-in on Outcomes in the BRCA1/2 Population.
  • At the final analysis⁷:
    • After a median follow-up of 37.3 months, no differences 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; 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=0.024). These endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
  • 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 TEAEs occurred in 15.1% of patients in the niraparib/AAP group and 5.7% of patients in the placebo/AAP group.⁵ Safety profiles at the final analysis⁷ and second interim analysis² were consistent with that of the first interim analysis, with no new safety signals observed.
• QUEST (NCT03431350) is an ongoing, phase 1b-2, multicenter, open-label study evaluating the safety, tolerability, and efficacy of niraparib in combination with other anticancer therapies, including cetrelimab (an investigational, intravenous, monoclonal antibody against programmed cell death receptor-1 [PD-1]) or AAP, for the treatment of mCRPC in patients with HRR mutations whose disease had progressed on prior ART therapy (including AAP and enzalutamide).^9-12
  • Efficacy results for niraparib/AAP are summarized in Table: Primary and Secondary Efficacy Endpoints: Combination 2 ITT Population. In the niraparib/AAP intent-to-treat (ITT) population (n=23), composite response rate (CRR) was 56.5% (90% CI, 37.5-74.2) after a median follow-up of 18 months. Objective response rate (ORR) was 50.0% (90% CI, 9.040.4), and median duration of response (DOR) was 4.7 months (range, 3.78.2).¹¹
  • A summary of TEAEs in the niraparib/AAP group is described below. In patients receiving niraparib/AAP, the most common TEAEs leading to dose interruption/reduction in 58.3% (n=14) of patients were anemia (n=7), thrombocytopenia (n=5), and neutropenia (n=3).¹² Serious treatment-related adverse events (TRAEs) were observed in 3 patients and included lower GI hemorrhage, asthenia and noncardiac chest pain, and anemia (n=1 each).¹¹
• BEDIVERE (NCT02924766) was a phase 1b, open-label, 2-part, multicenter, doseselection study evaluating the safety and pharmacokinetics (PK) of niraparib in combination with apalutamide or AAP conducted in patients with mCRPC who may or may not have DNA-repair gene defect (DRD) anomalies. All patients were previously treated with ≥1 line of prior taxane-based chemotherapy and ≥1 line of prior androgen receptor-axis-targeted therapy (ARAT; ie, enzalutamide, abiraterone, investigational, bicalutamide, flutamide, nilutamide, degarelix, cyproterone acetate) for prostate cancer.^13-16
  • No dose-limiting toxicities (DLTs) were observed in the niraparib 200 mg in combination with AAP group. Three DLTs were observed in the niraparib 300 mg in combination with AAP group (Table: Adverse Events).¹³
  • Niraparib 200 mg in combination with AAP was selected as the recommended phase 2 dose (RP2D). PK assessments reported no significant interaction between niraparib in combination with AAP (Table: PK Characteristics of NIRA and Abiraterone When NIRA Was Administered With AAP: PK-Evaluable Population).¹³
  • The DLTs observed in the niraparib 300 mg with AAP group led to the decision to discontinue all combinations containing niraparib 300 mg.¹³

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^1,5-7 and Efstathiou et al (2023)² 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 mutations, including BRCA1/2 (n=225).

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.¹
• A total of 225 patients with BRCA1/2 mutations were enrolled, of which 6 (5.3%) and 5 (4.5%) patients in the niraparib/AAP and placebo/AAP groups, respectively, received prior ART therapy for nmCRPC or mCSPC.⁵

Efficacy

• Efficacy analysis results were not specifically reported for patients who received prior ART therapy in the MAGNITUDE study.
• A summary of efficacy results for patients in the BRCA1/2 population is provided in Table: Prespecified Primary and Key Secondary Endpoints in the BRCA1/2 Population.
• At the second interim analysis, at a median prior AAP run-in treatment duration of 1.9 (range, 0.3-4.1) months, patients in the BRCA1/2 subgroup who received AAP for ≤2 months had a treatment benefit similar to that of patients who did not receive prior AAP. Patients in the BRCA1/2 subgroup who received prior AAP for >2-4 months did not show a rPFS benefit.⁸ Outcomes are shown in Table: Impact of AAP Run-in on Outcomes in the BRCA1/2 Population.

Safety

• Safety analysis results were not specifically reported for patients who received prior ART therapy in the MAGNITUDE study.
• At the final analysis^6,7:
  • The safety profile in the BRCA+ subgroup was consistent with that of the HRR+ population 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 analyses⁵ and the final analysis⁷ were consistent, with no new safety signals.

QUEST Study

Chi et al (2023)¹¹ reported the safety, tolerability, and efficacy of niraparib/AAP (combination 2) in patients (N=24) with mCRPC and HRR mutations whose disease had progressed on 1 prior line of ART therapy. Patients were assigned to receive 1 of 3 combination therapies, with niraparib PO as backbone therapy. Combination 2 included niraparib 200 mg (2 x 100 mg) PO once daily and abiraterone acetate 1000 mg (4 x 250 mg) PO once daily with prednisone 5 mg PO twice daily.^9-11 Results summarized below are limited to the niraparib/AAP group (combination 2).

The study design is presented in Figure: QUEST Study Design (Combination 2).

Results

Patient Characteristics

• A total of 24 patients with mCRPC were enrolled to receive combination 2 of niraparib/AAP.¹²
• Of the 24 enrolled patients, 8 patients had biallelic BRCA1/2 alterations, 9 patients had monoallelic BRCA1/2 alterations, and 6 patients had other monoallelic alterations.¹²
• In the safety population, 42% of patients had soft tissue or nodal metastasis and 29% of patients received prior docetaxel therapy.¹²

Efficacy

• Median treatment duration for niraparib/AAP was 10.3 months (range, 0.7-22.0).¹²
• CRR was 56.5% (90% CI, 37.5-74.2) in the ITT population (n=13) at a median followup of 18 months.¹¹ Primary and secondary efficacy endpoints are described in Table: Primary and Secondary Efficacy Endpoints: Combination 2 ITT Population.
  • A total of 8 patients remained on treatment at the analysis cutoff.
• Of 10 patients with measurable disease at baseline, 5 (50%) patients reached partial response (PR). Best responses of stable disease and progressive disease were seen in 2 (20%) patients and 3 (30%) patients, respectively. No patient experienced a complete response (CR).¹²
• ORR was 50.0% (90% CI, 9.0-40.4), and median DOR was 4.7 months (range, 3.78.2).¹¹
• Median rPFS was 11.0 months (9.7not estimable). At 3, 6, 9, and 12 months, event-free survival (EFS) rates were 85.1%, 74.1%, 74.1%, and 46.7%, respectively.¹²

Safety

• In the safety population (n=24), the most common TEAEs of any grade reported by ≥15% of patients were anemia, fatigue, constipation, thrombocytopenia, nausea, vomiting, decreased appetite, neutropenia, back pain, dyspnea, dizziness, and decreased weight.¹¹
  • The most common grade ≥3 AEs were anemia (41.7%), thrombocytopenia (20.8%), fatigue (16.7%), and neutropenia (12.5%).
• TEAEs led to dose interruption in 11 patients and dose reduction in 9 patients. Anemia (n=7), thrombocytopenia (n=5), and neutropenia (n=3) were the most cited reasons for dose interruptions/reductions.
• Discontinuation of niraparib/AAP therapy due to a TEAE occurred in 2 patients (thrombocytopenia [n=1]; thrombocytopenia and anemia [n=1]).
• A total of 3 patients in the combination 2 group experienced serious TRAEs, which included lower GI hemorrhage, asthenia and noncardiac chest pain, and anemia (n=1 each).¹¹
  • No deaths due to AEs were observed.

BEDIVERE Study

Saad et al (2021)^13-16 assessed the safety and PK of niraparib with AAP or apalutamide to determine the RP2D in patients with mCRPC (N=33) with or without HRR mutations who had received ≥1 line of prior taxane-based chemotherapy and ARAT. Results summarized below are limited to the niraparib/AAP group.

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

Results

Patient Characteristics

• In the niraparib/AAP group, 27 patients were enrolled:
  • Overall, 4 and 8 patients, respectively, received niraparib 200 mg and 300 mg with AAP in part 1.
  • An additional 15 patients received niraparib 200 mg in part 2.
  • Median follow-up duration was 9.0 (range, 0.6-23.9) months.
• All patients had received ≥2 lines of systemic therapy, including ≥1 line of ARAT and taxane therapy.

Safety

Niraparib 300 mg with AAP

• Of the 8 patients in the niraparib 300 mg with AAP group, 3 patients reported DLTs.
  • One patient reported 2 DLTs: grade 3 fatigue and grade 4 elevated
    gamma-glutamyl transferase
  • Two additional patients reported a DLT of grade 4 neutropenia at cycle 2 day 1 (C2D1).
• Grade 3/4 TEAEs were reported in 7 (87.5%) patients.
• Given 3 of 8 (37.5%) patients in the niraparib 300 mg with AAP group had DLTs (above the acceptable DLT limit of 33%), niraparib 300 mg with AAP was not assessed further.

Niraparib 200 mg with AAP

• No DLTs were reported in the niraparib 200 mg with AAP group.
• Grade 3/4 TEAEs were reported in 12 (63.1%) patients.
• In the 19 patients treated with niraparib 200 mg with AAP:
  • The most common grade 3/4 AEs were thrombocytopenia (26.3%), hypertension (21.1%), nausea (15.8%), vomiting (15.8%), anemia (10.5%), and hypophosphatemia (10.5%).
  • Any-grade TEAEs of special interest were thrombocytopenia (31.6%), hypertension (31.6%), anemia (26.3%), leukopenia (10.5%), and neutropenia (10.5%).
  • TEAE with outcome of death: 1 patient had general health deterioration; deemed unrelated.
• Niraparib 200 mg in combination with AAP was selected as the RP2D and was further evaluated in 15 additional patients in part 2.

AEs and incidence of TEAEs of special interest are reported in Table: Adverse Events.

Pharmacokinetics

PK results of Niraparib and its Metabolite M1

• Niraparib maximum plasma concentration (C_max) was achieved at a median of approximately 3 hours postdose at C1D1 and at 4 hours postdose at C2D1.
• Mean C_max values at C2D1 were approximately 2-fold greater compared with those at C1D1.
  • Values were greater with niraparib 300 mg vs 200 mg.
• Trends for mean area under concentration-time curve from 0 to 24 h (AUC_0-24) were generally similar, with greater values at C2D1 vs C1D1 and with niraparib 300 mg vs 200 mg.
• Niraparib C_max (1141 ng/mL) and AUC_0-24 (18,536 ng*h/mL) values at C2D1 with niraparib 300 mg coadministered with AAP were comparable to historical niraparib monotherapy data (C_max range, 582-2230 ng/mL; area under concentration-time curve from 0 h to the end of the dosing period [AUC_0-tau] range, 14,659-46,900 ng*h/mL) (Table: PK Characteristics of NIRA and Abiraterone When NIRA Was Administered With AAP: PK-Evaluable Population).
• M1 C_max was achieved at a median of 10 hours postdose at C1D1 and ~4-6 hours postdose at C2D1.
• Mean C_max values of M1 were greater at C2D1 vs C1D1 and with niraparib 300 mg vs 200 mg.
• Trends for M1 mean AUC_0-24 were generally similar, with greater values at C2D1 vs C1D1 (due to accumulation) and with niraparib 300 mg vs 200 mg.
• Metabolite-to-parent ratios were below 1 in all cohorts.

PK Results of Abiraterone

• Abiraterone C_max in patients who received niraparib 200 mg with AAP was achieved in a median of 1.35 hours postdose at C2D1.
• Mean AUC_0-24 was 712 ng*h/mL.
• Mean trough plasma concentration (C_trough) levels of abiraterone at C2D1 were slightly lower for niraparib 300 mg than for 200 mg.
• Summary statistics for abiraterone C_max, time to maximum plasma concentration (t_max), and AUC_0-24 in patients who received niraparib 300 mg with AAP could not be calculated because data were available for only 2 patients.
• PK results in patients who received niraparib with AAP are described in Table: PK Characteristics of NIRA and Abiraterone When NIRA Was Administered With AAP: PK-Evaluable Population.

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 14 August 2025. Summarized in this response are relevant data pertaining to this topic in patients with prostate cancer.