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. The primary endpoint is radiographic progressionfree 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 are described in Table: Prespecified Primary and Key Secondary Endpoints.
  • At the first interim analysis (IA1)³:
    • 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 analysis⁷:
    • 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) is described in Table: Summary of Most Common (≥10% in Either Group) TEAEs at IA2 (HRR+ Population). In the niraparib/AAP vs placebo/AAP group, grade ≥3 adverse events (AEs) were reported in 153 (72.2%) vs 104 (49.3%) patients in the second interim analysis (IA2) and 157 (74.1%) vs 108 (51.2%) patients in the final analysis. In the niraparib/AAP vs placebo/AAP group, TEAEs leading to discontinuation were reported in 18.4% vs 8.1% of patients in the final analysis.^6,7 Safety profiles at the final analysis and IA2 were consistent with those observed at the IA1, with no new safety signals reported.⁶ 
  • Additional analyses for inverse probability of treatment weighting analysis of time-to-event outcomes, gene-by-gene analysis in patients with mCRPC and a single-gene HRR alteration other than BRCA1/2, sensitivity analyses to evaluate the impact of AAP run-in treatment, health-related quality of life (HRQoL), pain, and tolerability, and stratified efficacy by outcomes of tissue vs plasma enrollment assay used to classify HRR+ have been evaluated.^8-13
• 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 entering in the mCRPC phase will be randomized to receive either standard of care (SOC) or an experimental treatment including abiraterone acetate, or niraparib/AAP based on predefined biomarker signatures. The study has a planned enrollment of 750 patients.^14,15 The efficacy and safety results have not been published.
• 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 either cetrelimab (an investigational, intravenous, monoclonal antibody against programmed cell death receptor-1) or AAP, for the treatment of mCRPC in patients with HRR gene alterations who experienced disease progression on prior androgen receptor-targeted (ART) therapy for prostate cancer. Primary endpoints were the incidence and severity of TEAEs and the composite response rate (CRR). Secondary endpoints included the circulating tumor cell (CTC) response rate, objective response rate (ORR), and rPFS.^16-18
  • In patients receiving niraparib/AAP, the most common TEAEs leading to dose interruption or reduction in 58.3% (n=14) of patients were anemia (n=7), thrombocytopenia (n=5), and neutropenia (n=3).¹⁹ Serious treatment-related adverse events (TRAEs) were observed in 3 patients and included lower gastrointestinal (GI) hemorrhage (n=1), asthenia and noncardiac chest pain (n=1), and anemia (n=1).¹⁸
  • Efficacy results for niraparib/AAP are summarized in Table: Primary and Secondary Efficacy Endpoints. In the niraparib/AAP intention-to-treat (ITT) population (n=23), CRR was 56.5% (90% CI, 37.5-74.2) after a median follow-up of 18 months. ORR was 50.0% (90% CI, 9.0-40.4), and the median duration of response (DOR) was 4.7 months (range, 3.7-8.2).¹⁸
  • Results for other niraparib combination therapies in the QUEST study have not been published.
• Results from a matching-adjusted indirect comparison (MAIC) study that utilized data from the following phase 3 registrational studies in patients with L1 mCRPC have been reported: MAGNITUDE (AKEEGA and androgen deprivation therapy [ADT] vs placebo/AAP and ADT; HRR+ population), PROpel (olaparib plus AAP and ADT vs placebo plus AAP and ADT; all-comers population), and TALAPRO-2 (talazoparib plus enzalutamide and ADT vs placebo plus enzalutamide and ADT; all-comers population).²⁰ 

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023, 2025)^3,4,6,7 and Efstathiou et al (2023)⁵ 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).^3,21
  • 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.³
• 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 subgroup⁴:
  • 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.
• In the HRR+ population⁴:
  • 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 PARP inhibitors 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.⁷ 
  • 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.
• Subsequent treatment in patients with disease progression is summarized in Tables: Subsequent Treatment (BRCA+ Subgroup) and Subsequent Treatment (HRR+ Population).

Safety

• 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).⁴ 
• 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.⁴

• At the final analysis,⁷  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 Tables: Safety Summary: Final Analysis (HRR+ Population) and TEAEs of Special Interest: Final Analysis (HRR+ Population).

• Safety profiles across IA1, IA2, and the final analysis were consistent, with no new safety signals.⁶ 

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, prostate-specific antigen [PSA] progression, or death) occurred.^21,23
  • 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 HR ≥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.²¹
• 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.²¹

ProBio Study

De Laere et al (2022)¹⁴ described the study design for an ongoing, phase 3, outcomeadaptive, multiarm, multiple-assignment, randomized, open-label, international biomarker-driven platform study in patients with de novo mHSPC or L1 mCRPC. The information summarized below is limited to the mCRPC treatment phase.

Study Design/Methods

• Patients with mCRPC will be randomized to receive either SOC or an experimental treatment including enzalutamide, or niraparib/AAP based on predefined biomarker signatures. Local therapy to the prostate will be allowed across all treatment arms.^14,15
• Patients were stratified by prespecified biomarker signatures (inferred from diagnostic tissue and/or liquid biopsy profiling), previous treatment, and fraction of circulating tumor DNA (ctDNA).¹⁴
• Patients allocated to the control arm will remain in the control arm throughout subsequent lines of therapy in the trial. Patients in the experimental arms will be rerandomized to investigational drugs (abiraterone acetate, enzalutamide, niraparib/AAP, docetaxel, cabazitaxel, or carboplatin) within a treatment class.¹⁴
• Key inclusion criteria: ≥18 years old; histologically confirmed prostate adenocarcinoma starting systemic therapy for metastatic disease, including L1 mCRPC; distant metastatic disease documented by positive bone scan or metastatic lesions on CT/MRI; adequate health and hematologic, hepatic, and renal functions, as assessed by investigator; albumin ≥28 g/L; ECOG PS 0-2.^14,15
• Key exclusion criteria: other malignancies within 5 years except nonmelanoma skin cancer; myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke, transient ischemic attack, or New York Heart Association class III or IV congestive heart failure ≤6 months prior to randomization; uncontrolled hypertension. Specific criteria for the mCRPC phase included undetectable levels of ctDNA; prior systemic therapy (except standard ADT).^14,15
• Primary endpoint: to determine whether a biomarker signature and treatment combination is superior to SOC with respect to PFS.^14,15
• Secondary endpoints: to determine whether biomarker-driven treatment selection can improve PFS for the experimental arms combined vs the control arm and whether a treatment class is superior for a certain biomarker signature by comparing the experimental arms against each other.¹⁴
• Other secondary endpoints: PSA PFS, rPFS, response rates, PFS2, OS, quality of life, health economics, drug safety, and identification of new biomarkers and superior treatment sequencing regimens.^14,15

The efficacy and safety results of the ProBio study have not been published.

QUEST Study

Chi et al (2023)¹⁸ reported the safety, tolerability, and efficacy of niraparib/AAP (combination 2) in patients with mCRPC and HRR gene alterations who experienced disease progression on 1 prior line of ART therapy.

Study Design/Methods

• Ongoing, phase 1b-2, multicenter, open-label study.^16,18
• In this study, designed as a master protocol, patients were assigned to receive 1 of the following 3 combination therapies, with oral niraparib as a backbone therapy:
  • Combination 1: niraparib 200 mg orally PO once daily + cetrelimab 480 mg intravenously every 4 weeks.^16,17
  • Combination 2: niraparib 200 mg (2 × 100 mg) PO once daily + abiraterone acetate 1000 mg (4 × 250 mg) PO once daily + prednisone 5 mg PO twice daily.^16-18
  • Combination 3: niraparib with abiraterone acetate for pharmacokinetics assessment.¹⁶
• In part 1 of the study, the recommended phase 2 dose for combination 1 was established and incidence of specified toxicities was determined.^16,17
• In part 2 of the study, antitumor activity and safety of combination 1 and combination 2 were evaluated.
  • Combination 1 patients were assigned to cohort 1A or cohort 1B if they were DNA repair gene defect (DRD) positive or DRD negative, respectively.¹⁷
  • Combination 2 patients were divided into 3 cohorts depending on whether they had biallelic BRCA1/2 HRR alterations, monoallelic BRCA1/2 HRR alterations, or monoallelic other HRR alterations.
• The study will also determine the relative bioavailability of combination 3.¹⁶
• The study design for combination 2 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. Select patient baseline characteristics are described in Table: Select Baseline Characteristics: Combination 2 Safety Population.
• Of the 24 enrolled patients, 8 had biallelic BRCA1/2 alterations, 9 had monoallelic BRCA1/2 alterations, and 6 had monoallelic other alterations.¹⁹
  • Initially, 1 HRR- patient was assigned to the monoallelic BRCA1/2 cohort in error. This patient was excluded from the ITT population but was included in the safety population.
• In the safety population, 42% of patients had soft tissue or nodal metastasis and 29% of patients received prior docetaxel therapy.¹⁹

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, back pain, dizziness, and weight decreased.¹⁸
  • 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 interruption or reduction. ¹⁸
• Discontinuation of niraparib/AAP therapy due to TEAEs 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 consisted of lower GI hemorrhage (n=1), asthenia and noncardiac chest pain (n=1), and anemia (n=1).
  • No deaths due to AEs were observed.

Efficacy

• The median treatment duration for patients receiving niraparib/AAP was 10.3 months (range, 0.7-22.0).
• CRR was 56.5% (90% CI, 37.5-74.2) in the ITT population (n=13) at a median followup of 18 months.¹⁸ Primary and secondary efficacy endpoints are described in Table: Primary and Secondary Efficacy Endpoints: Combination 2 ITT Population.
  • A total of 8 patients remained under treatment at the analysis cutoff.
• Of 10 patients with measurable disease at baseline, 5 (50%) experienced a partial response. The best responses of stable disease and progressive disease were experienced by 2 (20%) patients and 3 (30%) patients, respectively. No patient experienced a complete response.
• ORR was 50.0% (90% CI, 9.0-40.4), and the median DOR was 4.7 months (range, 3.78.2).
• The median rPFS was 11.0 months (90% CI, 9.7-not estimable). At 3, 6, 9, and 12 months, event-free survival rates were 85.1%, 74.1%, 74.1%, and 46.7%, respectively.¹⁹

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 09 October 2025.