SUMMARY  

• MAGNITUDE (NCT03748641) is a phase 3, randomized, double-blind, placebocontrolled, global study evaluating the efficacy and safety of AKEEGA with prednisone compared to 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). Key secondary endpoints include time to cytotoxic chemotherapy (TCC), time to symptomatic progression (TSP), and overall survival (OS).^1-4
  • 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 primary and key secondary endpoint results are described in Table: Prespecified Primary and Key Secondary Endpoints.
  • At the first interim analysis³:
    • 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 with 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 second interim analysis⁵:
    • Across all BRCA1/2 patients, at a median follow-up of 24.8 months, a total of 43 death events occurred in the niraparib/AAP group compared to 49 events in the placebo/AAP group (HR, 0.88; 95% CI, 0.581.34; nominal P=0.5505). These endpoints were not adjusted for multiple comparisons. Therefore, the Pvalues displayed are nominal, and statistical significance has not been established.
  • At the final analysis⁶:
    • 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.
    • An inverse probability of treatment weighting analysis of time-to-event outcomes using data from patients with BRCA1/2-altered mCRPC revealed a greater median OS in the niraparib/AAP group vs the placebo/AAP group (34.1 months vs 27.4 months; HR, 0.65; 95% CI, 0.46-0.93; P=0.017).⁷
  • 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 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 analysis⁶ and second interim analysis⁴ were consistent with that of the first interim analysis, with no new safety signals observed.
  • Results from a prespecified gene-by-gene analysis evaluating the efficacy of niraparib/AAP in 186 patients with single-gene HRR alteration, other than BRCA1/2, have been reported.⁸
  • Health-related quality of life and pain, respectively, were evaluated in terms of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain InventoryShort Form (BPI-SF) score changes from baseline.^9,10
• 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.^11,12 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.^13-15
  • 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).¹⁶ 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).¹⁵
  • 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).¹⁵
  • Results for other niraparib combination therapies in the QUEST study have not been published.

CLINICAL DATA

MAGNITUDE Study

Chi et al (2023)^3,5,6 and Efstathiou et al (2023)⁴ reported the efficacy and safety of AKEEGA with prednisone compared to 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

• Ongoing, phase 3, randomized, double-blind, placebo-controlled, global study.³
• In cohorts 1 and 2, patients were randomized 1:1 to receive niraparib 200 mg by mouth (PO) once daily or matching placebo in combination with abiraterone acetate 1000 mg PO once daily plus prednisone 5 mg twice daily.³
• 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).^3,17
  • 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 PO once daily with prednisone 5 mg twice daily.³
• Patients were stratified by prior taxane-based chemotherapy for metastatic castrationsensitive prostate cancer (mCSPC), prior androgen receptor (AR) inhibitor therapy for non-metastatic castration-resistant prostate cancer (nmCRPC) or mCSPC, prior AAP for L1 mCRPC, and BRCA1/2 vs other HRR gene alterations (HRR+ cohort).²
• 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 ECOG PS of 1 were imbalanced to the disadvantage of the niraparib/AAP group.³
• Select baseline patient characteristics in the BRCA+ population are shown in Table: Select Baseline Patient Characteristics: BRCA+ Population.

HRR+ Cohort

Efficacy

• A summary of results for the patients in the HRR+ cohort is provided in Table: Prespecified Primary and Key Secondary Endpoints.
• At the first interim analysis³:
  • A statistically significant improvement in BICR-assessed median rPFS was observed in the niraparib/AAP group compared with the placebo/AAP group for patients with BRCA1/2 mutations (median follow-up: 16.7 months) and HRR+ patients (median follow-up: 18.6 months) as shown in Table: Prespecified Primary and Key Secondary Endpoints.
• At the second interim analysis, at 8.1 months of additional follow-up from the first interim analysis, the following endpoints were evaluated.⁵ 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, 0.390.78; nominal P=0.0007).
  • In all HRR+ patients, a statistically significant improvement in BICR-assessed median rPFS was observed in the niraparib/AAP group compared with the placebo/AAP group: 16.7 months vs 13.7 months (HR, 0.76; 95% CI, 0.60-0.97; P=0.0280). No formal statistical testing was performed for rPFS in all HRR+ patients as the endpoint was previously found to be statistically significant in the first interim analysis.
  • 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.
  • In all HRR+ patients, a statistically significant prolongation in both TCC (HR, 0.67; 95% CI, 0.47-0.94; P=0.0206) and TSP (HR, 0.60; 95% CI, 0.42-0.84; P=0.0029) was observed in patients treated with niraparib/AAP compared with placebo/AAP.⁵
  • At a median follow-up of 24.8 months in the BRCA1/2 population, there was a trend in stratified analysis toward improved OS with niraparib/AAP. A total of 43 death events occurred in the niraparib/AAP group compared with 49 events in the placebo/AAP group (HR, 0.88; 95% CI, 0.58-1.34; nominal P=0.5505).⁴
    • 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, 0.45-1.05; nominal P=0.0793 and HR, 0.54; 95% CI, 0.33-0.90; nominal P=0.0181, respectively).
  • At a median follow-up of 26.8 months in the HRR+ population, the OS data were immature with 72.8% of the required death events for the final analysis observed. In the OS stratified analysis, HR was 1.01 (95% CI, 0.75-1.36; P=0.9480).
    • After adjusting for baseline characteristics in a multivariate analysis and accounting for differences in subsequent therapies in an IPCW analysis, OS improvement was observed with niraparib/AAP compared with placebo/AAP in the HRR+ population (HR, 0.82; 95% CI, 0.60-1.10; nominal P=0.1821 and HR, 0.70; 95% CI, 0.49-0.99; nominal P=0.0414, respectively).
• At the final analysis, 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).⁶ 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.

Safety

• At the second interim analysis, 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.⁵
  • 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 the 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 analysis⁶:
  • 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 analyses⁵ and the final analysis⁶ were consistent, with no new safety signals.

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 either rPFS, prostate-specific antigen [PSA] progression, or death) occurred.¹⁷
  • The composite progression endpoint (n=233) met the futility criteria (HR, 1.09; 95% CI, 0.75-1.59), where futility was defined as ≥1.
  • There were 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) that occurred.
• Additional grade 3/4 toxicity was observed in the niraparib/AAP group compared with the placebo/AAP group.¹⁷
• Based on the efficacy and safety results in patients with HRR- mCRPC, the independent data monitoring committee (IDMC) recommended stopping enrollment in this cohort to support patient safety and prevent overtreatment.¹⁷

ProBio Study

De Laere et al (2022)¹¹ 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.^11,12
• 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).¹¹
• 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.¹¹
• 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.^11,12
• 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).^11,12
• Primary endpoint: to determine whether a biomarker signature and treatment combination is superior to SOC with respect to PFS.^11,12
• 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.¹¹
• 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.^11,12

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

QUEST Study

Chi et al (2023)¹⁵ 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.^13,15
• 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.^13,14
  • 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.^13-15
  • Combination 3: niraparib with abiraterone acetate for pharmacokinetics assessment.¹³
• In part 1 of the study, the recommended phase 2 dose for combination 1 was established and incidence of specified toxicities was determined.^13,14
• 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.¹⁴
  • 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 3.¹³
• 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.¹⁶
  • 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.¹⁶

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.¹⁵
  • 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. ¹⁵
• 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.¹⁵ 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.¹⁶

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 25 September 2024.