Summary

• In an exposure-response (E-R) analysis of the MAGNITUDE study, the relationship between niraparib exposure and selected efficacy and safety endpoints was evaluated in patients with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene alterations.¹
  • For all steady-state average drug concentration (C_avg) quartiles of niraparib vs placebo, the HR was <1; however, an E-R relationship was not seen.
  • In the logistic regression analysis of anemia, niraparib exposure was a statistically significant predictor of response (P<0.001) while abiraterone exposure was not a statistically significant predictor of response.
    • The probability of experiencing grade 3 or 4 anemia increased with increasing niraparib exposure (steady state area under the plasma concentration-time curve from 0 to 24 hours, AUC_0-24h [µg.h/mL]; OR, 1.168 [95% CI, 1.133-1.206]; P<0.001).
• In a phase 1b, open-label, 2-part, multicenter, dose-selection study (BEDIVERE) in patients with mCRPC, after administration of 200 mg or 300 mg of niraparib in combination with 1000 mg of abiraterone acetate (given as single agents once daily) with 5 mg prednisone twice daily, the steady state maximum plasma concentration (C_max) of niraparib were 985 and 1141 ng/mL, respectively. The AUC_0-24h values of niraparib at 200 mg and 300 mg were 17,745 and 18,536 ng*h/mL, respectively. These values were consistent with exposures observed for niraparib monotherapy. The abiraterone pharmacokinetics (PK) for the combination were also comparable to abiraterone acetate 1000 mg monotherapy data.²
• In an open-label, randomized, multicenter, bioequivalence (BE)/bioavailability (BA) study, BE and BA were assessed in patients with mCRPC under modified fasting conditions.³
  • The regular-strength (RS) dual action tablet (DAT) formulation of niraparib/abiraterone acetate met BE criteria with respect to the single-agent combination (SAC) formulation of niraparib and abiraterone acetate at steady state.
  • The low-strength (LS) DAT formulation was considered to be BE to SAC based on select BE criteria being met for niraparib and abiraterone acetate with additional results from paired analyses and model-based BE assessments.
• In a population pharmacokinetics (PPK) and BE study, niraparib and abiraterone acetate were evaluated after being administered alone or in combination (either as single agents or as RS and LS DAT). The probability of LS DAT to meet the BE criteria (90% CI of geometric mean ratio [GMR] for AUC_0-24h and C_max within the 80-125% range) compared with SAC (100 mg niraparib and 1000 mg abiraterone acetate) was also evaluated via clinical trial simulations.⁴
  • The covariates identified for niraparib were creatinine clearance (CrCl) on oral clearance (CL); LS DAT on zero-order drug release (D1) and apparent oral bioavailability (F1); HRR status on CL; race on firstorder absorption rate constant (KA), intercompartmental clearance, and volume of distribution of the peripheral compartment. For abiraterone, RS DAT was a covariate of KA, D1, and F1. Dose adjustments by these covariates were not warranted as none had a clinically relevant impact on niraparib and abiraterone acetate exposure.
  • The average GMRs (LS DAT vs SAC) for niraparib AUC_0-24h and C_max were 88.2% and 88.7%, respectively, and for abiraterone acetate AUC_0-24h and C_max were 100% and 98.7%, respectively.

CLINICAL DATA

MAGNITUDE Study

Boulton et al (2023)¹ evaluated the relationship between niraparib exposure and selected efficacy and safety endpoints from the MAGNITUDE study in patients with mCRPC with or without HRR gene alterations. The study also evaluated the adequacy of the intended clinical dose recommendation of niraparib. The information summarized below is limited to the PK of the niraparib/abiraterone acetate with prednisone (AAP) group.

Study Design/Methods

• Phase 3, double-blind, placebo-controlled study
• Included patients with (cohort 1) and without (cohort 2) HRR gene alterations:
  • Efficacy-evaluable patients (cohort 1; n=212)
  • Efficacy-evaluable patients with BRCA gene alterations (cohort 1; n=113)
  • Safety-evaluable patients (cohort 1; n=206)
  • Safety-evaluable patients (cohort 2; n=120)
• Select endpoints:
  • Efficacy: radiographic progression-free survival (rPFS) by central review
  • Safety: grade ≥3 hematological toxicity (including thrombocytopenia, anemia, and/or neutropenia), nausea, hypertension, hypokalemia, fluid retention/edema, and hepatotoxicity
  • Exposure: C_avg (efficacy) and AUC_0-24h (safety) based on post hoc estimates from the final PPK model and scaled by the average daily dose up to the time of the first event of interest (rPFS event, treatment-emergent adverse event [TEAE], end of treatment, or censoring date)

Results

Pharmacokinetics

• For all C_avg quartiles vs placebo, HR was <1; however, an E-R relationship was not seen (Table: Relationship Between Niraparib Exposure and rPFS in the Full HRR Analysis Set [E-R Model]).
• Similar results were seen in a subgroup analysis that only included patients with BRCA gene alterations.
• The authors concluded that niraparib 200 mg provided consistent benefit to patients across the range of exposures that were evaluated.

• Among the preselected safety endpoints, anemia was the only TEAE that met the predefined criteria (overall incidence ≥10%, and significant difference between the incidences in the treatment groups based on a nominal P-value <0.05) to apply the E-R analysis.
  • Grade 3 or 4 anemia was reported in 21% of patients.
  • In the NIRA/AAP group, anemia was reported in 35% of patients.
• Other TEAEs did not meet one or both predefined criteria for application of E-R analysis (thrombocytopenia and neutropenia, hypertension, nausea, hypokalemia, fluid retention/edema, and hepatotoxicity).
• In the logistic regression analysis of anemia, niraparib exposure was a statistically significant predictor of response (P<0.001), while abiraterone exposure was not a statistically significant predictor of response.
  • The probability of experiencing grade 3 or 4 anemia increased with increasing niraparib exposure (AUC_0-24h [µg.h/mL]; OR, 1.168; 95% CI, 1.133-1.206; P<0.001).
    • Treatment discontinuation due to anemia was reported in 7 (1%) patients in the niraparib/AAP group (cohort 1, n=5; cohort 2, n=2).
• Similar results were observed in the logistic regression analysis of hematological toxicity (as a combined class of events) as a function of niraparib (AUC_0-24h [µg.h/mL]; OR, 1.16; 95% CI, 1.128-1.195; P<0.001).
• The incidence of grade 3 or 4 anemia with the 100 mg and 200 mg daily doses of niraparib was predicted to be 16.7% (95% CI, 12.8-20.8) and 37.2% (95% CI, 30.843.6), respectively.
• The treatment effect explained by niraparib exposure was estimated to be 2.6 times higher than that unexplained by exposure.

BEDIVERE Study

Saad et al (2021)² assessed the PK of niraparib with apalutamide or AAP to determine the recommended phase 2 dose (RP2D) in patients with mCRPC (N=33). The information summarized below is limited to the PK of niraparib/AAP group.

Study Design/Methods

• Phase 1b, open-label, 2-part, multicenter safety and PK study
• Part 1 (dose escalation; standard 3+3 design):
  • Patients received daily oral niraparib 200 mg or 300 mg in combination with daily abiraterone acetate 1,000 mg with prednisone 5 mg twice daily or apalutamide 240 mg daily.
    • Niraparib with abiraterone acetate with the first daily dose of prednisone 5 mg were to be taken on an empty stomach. No food or liquids were to be consumed ≥2 hours before and ≥1 hour after dosing.
    • Niraparib and apalutamide were taken in the morning with or without food, except on the PK sampling days, when the drugs were taken at the study site after an overnight fast starting at midnight.
• Part 2 (dose expansion phase):
  • Patients received niraparib 200 mg or 300 mg in combination with AAP.
• Key inclusion criteria: men with mCRPC with or without DNA-repair anomalies; received ≥1 line of prior taxane-based chemotherapy and androgen-receptor-axis-targeted therapy (ARAT); surgical or medical castration (testosterone levels ≤50 ng/dL); prostate cancer progression by prostate specific antigen (PSA) progression according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria or radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Key exclusion criteria: Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2; presence of brain metastasis; prior treatment with a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor; radiotherapy ≤15 days prior to starting treatment
• Part 1 endpoints:
  • RP2D, determined from safety data as the dose at which fewer than one-third of patients experienced a dose limiting toxicity (DLT) and if significant drug-drug interactions (DDIs) were observed, a niraparib dose with an exposure comparable to or lower than that of historical niraparib 300 mg monotherapy data
  • PK of niraparib in combination with AAP or apalutamide, including C_max, AUC_0-24h, and trough concentration (C_trough)
• Part 2 endpoints:
  • Adverse events (AEs) and DLTs
  • PK of niraparib in combination with AAP, including C_max, AUC_0-24h, and C_trough

Results

Patient Characteristics

• In the niraparib/AAP group, a total of 27 patients were enrolled:
  • Four 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.
  • The median follow-up duration was 9.0 (range, 0.6-23.9) months.

Pharmacokinetics

Niraparib/AAP group

PK results of niraparib

• Mean C_max values at C2D1 were approximately 2-fold greater compared with C1D1.
  • Values were greater with niraparib 300 mg vs 200 mg.
• Trends for mean AUC_0-24h were generally similar, with greater values for C2D1 vs C1D1 and for niraparib 300 mg vs 200 mg.
• Niraparib C_max (1141 ng/mL) and AUC_0-24h (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; steady state area under the plasma concentration-time curve from 0 hours to the end of the dosing period [AUC_0-tau] range 14,659-46,900 ng*h/mL) (Table: PK Parameters of Niraparib and Abiraterone When Niraparib was Administered With AAP: PK-Evaluable Population).

PK results of abiraterone

• Mean AUC_0-24h was 712 ng*h/mL.
• Mean C_trough levels of abiraterone at C2D1 were slightly lower for niraparib 300 mg vs 200 mg.
• Summary statistics for abiraterone C_max and AUC_0-24h 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 Parameters of Niraparib and Abiraterone When Niraparib was Administered With AAP: PK-Evaluable Population).

BA/BE Study

Yu et al (2024)³ evaluated the BE of RS DAT formulation of niraparib/abiraterone acetate at steady state and the relative BA of LS DAT formulation of niraparib/abiraterone acetate after single-dose administration with respect to SAC of niraparib and abiraterone acetate in patients with mCRPC under modified fasting conditions (N=136).

Study Design/Methods

• Open-label, randomized, multicenter study
• Reference treatment (SAC):
  • 100 mg niraparib given as a 1x100 mg capsule and 1000 mg abiraterone acetate given as 4x250 mg tablets, administered orally as a daily dose
  • 200 mg niraparib given as 2x100 mg capsules and 1000 mg abiraterone acetate given as 4x250 mg tablets, administered orally as a daily dose
• Test treatment (DAT formulations):
  • LS DAT: niraparib 100 mg/abiraterone acetate 1000 mg given as 2xDAT tablets (niraparib 50 mg/abiraterone acetate 500 mg), administered orally as a daily dose
  • RS DAT: niraparib 200 mg/abiraterone acetate 1000 mg given as 2xDAT tablets (niraparib 100 mg/abiraterone acetate 500 mg), administered orally as a daily dose
• A randomized two-way crossover, multiple-dose design was used for the RS DAT BE study followed by a multiple-dose extension phase, while a single-dose run-in period was used for the LS DAT relative BA assessment.
• All patients were randomly assigned to 1 of the 4 treatment sequences that comprised 3 treatment periods used for PK assessment:
  • Period 1: single dose of niraparib 100 mg/abiraterone acetate 1000 mg on study day -7 as either LS DAT or SAC
  • Period 2: daily dose of niraparib 200 mg/abiraterone acetate 1000 mg from study days 1-11 as either RS DAT or SAC
  • Period 3: daily dose of niraparib 200 mg/abiraterone acetate 1000 mg from study days 12-23 as either RS DAT or SAC, whichever was not taken in period 2
  • From period 2 onward, patients received niraparib/abiraterone acetate in combination with prednisone/prednisolone 5 mg twice daily.
• In the extension phase (day 23 to discontinuation), patients continued on SAC or abiraterone acetate alone. Patients received study treatment until disease progression, withdrawal of consent, loss to follow-up, lack of clinical benefit, start of subsequent anticancer therapy, or until the sponsor ended the study.
• Endpoints: PK, pharmacodynamics (PD), and safety
• Pharmacokinetics:
  • The primary PK parameters for the BE assessment included maximum observed analyte concentration at steady state (C_max,ss) and area under the plasma concentration-time curve from time 0 to 24 hours at steady state (AUC_0-24h,ss). To meet the BE criteria, the 90% CI for the GMRs of RS DAT over SAC had to fall within the limit of 80-125%.
  • The primary PK parameters for the relative BA assessment included C_max and area under the plasma concentration-time curve from time 0 to 72 hours postdosing (AUC_0-72h) for niraparib and abiraterone. The GMRs and associated 90% CI for the primary PK parameters between LS DAT and SAC formulations were derived. Additionally, paired analyses of abiraterone in the LS DAT vs SAC were performed to further assess the relative BA within the same patients.
  • LS DAT was also evaluated for BE vs SAC using a preplanned clinical trial simulation and PPK models based on available PK data for niraparib and abiraterone. Simulated exposure parameters C_max,ss and AUC_0-24,ss for study days 11 and 22 were evaluated and BE criteria was met if 90% CI for the GMRs of LS DAT over SAC fell within the limit of 80-125%.

Results

Patient Characteristics

• Of the 136 patients who received at least 1 dose of study treatment, a total of 117 BEevaluable patients were included in the BE analysis and 134 PKevaluable patients were included in the relative BA analysis.
• Patients were primarily White (99.3%), and the median age was 67 years (range, 5090).

Pharmacokinetics

• Multiple-dose RS DAT was confirmed to be bioequivalent to SAC. The 90% CIs for the GMRs of C_max,ss and AUC_0-24h,ss for niraparib and abiraterone were within the 80-125% criteria for BE vs SAC (Table: Bioequivalence of RS DAT and SAC).
• The GMRs of C_max and AUC_0-72h for niraparib between LS DAT and SAC after a single administration were 90.88% and 90.11%, respectively, and the 90% CIs included 100% for both C_max and AUC_0-72h. Although the lower bound of the 90% CI for C_max marginally missed the BE criteria, the 90% CI for AUC_0-72h was within the 80-125% criteria for BE (Table: Relative BA of LS DAT and SAC: Parallel-Group Data).
• The GMRs of C_max and AUC_0-72h for abiraterone between LS DAT and SAC after a single administration were 132.62% and 121.93%, respectively, and the 90% CIs did not include 100%. In an additional paired data analysis for abiraterone between LS DAT and SAC, the GMRs of C_max and AUC were 100.54% and 102.58%, respectively, and the 90% CIs for both C_max and AUC were within the 80125% criteria for BE (Table: Relative BA for Abiraterone: Paired Data).
• Preplanned clinical trial simulations based on PPK model parameters showed that BE criteria would be met for C_max and AUC of both niraparib and abiraterone in 96.4% of simulations for LS DAT vs SAC.

PPK and BE Study

Russu et al (2023)⁴ evaluated the PPK of niraparib (n=916) and abiraterone (n=954), administered alone or in combination (either as single agents or as RS and LS DAT). The study also evaluated the probability of LS DAT vs SAC (100 mg niraparib and 1000 mg abiraterone acetate) to meet the BE criteria (ie, 90% CI of GMR for both AUC_0-24h and C_max within the 80-125% range) via clinical trial simulations.

Study Design/Methods

• PPK modeling and covariate analysis were conducted using pooled PK data from patients with mCRPC enrolled in the BEDIVERE, GALAHAD, QUEST, and MAGNITUDE studies, as well as a relative BA/BE study.
  • In all studies except GALAHAD (where niraparib was given as monotherapy), AAP was given alone or in combination with niraparib.
• BE clinical trial simulations for LS DAT vs SAC were performed based on niraparib and abiraterone PPK models.
  • The probability of demonstrating BE for LS DAT vs SAC was calculated as the proportion of simulated replicates in which the BE criteria were met (for AUC_0-24h and C_max) for both niraparib and abiraterone.

Results

PPK Modeling and Covariate Analysis

• The PK of niraparib and abiraterone were adequately described by an open 2compartment model with linear elimination and sequential zero-first order absorption (with 2 transit compartments for abiraterone).
• The covariates identified for niraparib were CrCl on CL, LS DAT on D1 and F1, HRR status on CL, race on KA, intercompartmental clearance, and volume of distribution of the peripheral compartment. For abiraterone, RS DAT was a covariate of KA, D1, and F1 (Table: Estimates of Identified Covariates of Final Niraparib and Abiraterone PPK Models).
  • Dose adjustments by these covariates were not warranted as none had a clinically relevant impact on niraparib and abiraterone exposure (Table: AUC_0-24h for Final Niraparib and Abiraterone PPK Models).
• Numerical predictive checks suggested a good agreement between the observed and simulated 5^th, 50^th, and 95^th percentiles of AUC_0-24h and C_max for singleagent administration, RS DAT, and LS DAT.

BE Clinical Trial Simulations

• A prefinal abiraterone PPK model that included the effects of LS DAT on KA (20% decrease vs SAC) and D1 (34% decrease vs SAC) was used for the simulated BE assessment of LS DAT since the final abiraterone PPK model did not contain any effect of LS DAT on absorption parameters (ie, not retained due to large relative standard errors).
• The average GMRs for LS DAT vs SAC for niraparib AUC_0-24h and C_max were 88.2% and 88.7%, respectively, and for abiraterone AUC_0-24h and C_max were 100% and 98.7%, respectively.
• The probability of demonstrating BE for LS DAT vs SAC was 96.4%.

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 04 June 2024.Summarized in this response are relevant data pertaining to this topic in patients with prostate cancer.