Summary

• BEDIVERE (NCT02924766) was a phase 1b, open-label, 2-part, multicenter, dose selection study evaluating the safety and pharmacokinetics (PK) of niraparib in combination with apalutamide (APA) or abiraterone acetate plus prednisone (AAP) conducted in men with metastatic castration-resistant prostate cancer (mCRPC) who may or may not have DNA-repair gene defect (DRD) anomalies.^1-4
• No dose-limiting toxicities (DLTs) were observed in the niraparib 200 mg in combination with AAP or APA groups. Three and 2 DLTs were observed in the niraparib 300 mg in combination with AAP and APA groups, respectively (Table: Adverse Events).¹
• 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 Parameters in Niraparib and Abiraterone When Niraparib was Administered With AAP: PK-Evaluable Population). The niraparib 200 mg + APA combination demonstrated reduced niraparib exposure compared to monotherapy (Table: PK Characteristics of Niraparib and Apalutamide When Niraparib was Administered With APA (C1D28): PK-Evaluable Population).¹
• The DLTs observed in the niraparib 300 mg combinations with AAP and APA groups, and the drug-drug interaction (DDI) observed with niraparib 200 mg plus APA group led to the decision to discontinue all niraparib 300 mg combinations and the niraparib 200 mg + APA combination.¹

CLINICAL DATA

BEDIVERE Study

Saad et al (2021)¹ assessed the safety and PK of niraparib with APA or AAP to determine the RP2D in patients with mCRPC (N=33).

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 (AA) 1000 mg plus prednisone 5 mg twice daily or APA 240 mg daily.
    • Niraparib with AA plus the first daily dose of prednisone 5 mg were to be taken on an empty stomach. No food or liquids were to be consumed for at least
      2 hours before and at least 1 hour after dosing.
    • Niraparib and APA 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.
  • DLTs were collected and analyzed during the first cycle (28 days).
• Part 2: Dose expansion phase
  • Patients received niraparib 200 mg or 300 mg in combination with AAP
• Serial blood samples were collected in Parts 1 and 2 on day 1 of cycles 1, 2, and 3, and every 3 cycles thereafter.
• 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 (ECOG) performance status ≥2; presence of brain metastasis; prior treatment with a poly (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 DLT and if significant 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 APA, including maximum plasma concentration (C_max), time to maximum plasma concentration (T_max), area under the plasma concentration time curve over the last 24h dosing interval (AUC_0-24h), trough concentration (C_trough), and metabolite to parent ratio for AUC_0-24h
• Part 2 Endpoints:
  • AEs and DLTs
  • PK of niraparib in combination with AAP, including C_max, T_max, AUC_0-24h, C_trough, and metabolite to parent ratio for AUC_0-24h

Results

Patient Characteristics

• In the niraparib + APA group, a total of 6 patients were enrolled:
  • Three patients each received niraparib 200 mg or 300 mg with APA in Part 1.
  • The median follow-up duration was 15.8 months (range, 10.6-22.4 months)
• 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 months (range, 0.6-23.9 months).
• Patient demographics and baseline characteristics were generally similar between the two groups (Table: Baseline Demographic and Clinical Characteristics).
• All patients had received ≥2 lines of systemic therapy, including ≥1 line of ARAT and taxane therapy.

Treatment Exposure and Dose Adjustments

Niraparib + APA Group

• The median number of treatment cycles administered was 6.0 and 1.0 in the niraparib
  200 mg and 300 mg cohorts, respectively (Table: Treatment Exposure and Dose Adjustments for Niraparib: Safety Population).
• The median treatment duration was 4.7 months in the 200 mg cohort and 0.9 months in the 300 mg cohort.
  • One patient in the 200 mg cohort received treatment for ≥6 months.

Niraparib + AAP Group

• The median number of treatment cycles administered was 4.0 and 4.5 in the niraparib
  200 mg and 300 mg cohorts, respectively (Table: Treatment Exposure and Dose Adjustments for Niraparib: Safety Population).
• The median treatment duration was 3.7 months in both cohorts.
  • Four patients each in the 200 mg and 300 mg cohorts received treatment for
    ≥6 months, including 1 patient each in the 200 mg and 300 mg cohorts who received treatment for ≥21 and ≥11 months, respectively.

Safety

Niraparib + APA Group

Niraparib 300 mg + APA

• Of the 3 patients in the niraparib 300 mg + APA group, 2 patients (66.7%) reported DLTs, which included grade 4 thrombocytopenia (n=1), grade 3 fatigue, and grade 3 hypertension (n=1).
• Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 3 patients (100%) in the 300 mg cohort (Table: Adverse Events).

Niraparib 200 mg + APA

• No DLTs were reported in the niraparib 200 mg + APA group.
• Grade 3/4 TEAEs were reported in 2 patients (66.7%) in the 200 mg cohort (Table: Adverse Events)

All six patients in the niraparib + APA group died due to progressive disease; however, none of the deaths occurred during treatment, and no deaths were attributed to TEAEs.  

Due to DLTs and PK results (described below), the combination of niraparib + APA was not further assessed in Part 2.

Niraparib + AAP Group

Niraparib 300 mg + AAP

• Of the 8 patients in the niraparib 300 mg + 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 patients (87.5%).
• Given 3 of 8 patients (37.5%) in the niraparib 300 mg + AAP group had DLTs (above the acceptable DLT limit of 33%), the niraparib 300 mg in combination with AAP was not further assessed.

Niraparib 200 mg + AAP

• No DLTs were reported in the niraparib 200 mg + AAP group.
• Grade 3/4 TEAEs were reported in 12 patients (63.1%).
• In the 19 patients treated with niraparib 200 mg + AAP:
  • 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: one patient had general health deterioration; deemed unrelated.
• Niraparib 200 mg was selected as the RP2D in combination with AAP 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

Niraparib + APA group

PK results of niraparib and its metabolite M1

• Mean C_max (315 ng/mL) of niraparib 200 mg when administered with APA was achieved in a median 3.0 hours postdose at cycle 1 day 28 (C1D28), with a biphasic decline thereafter.
• Mean AUC_0-24 in the niraparib 200 mg cohort was 4388 ng*h/mL.
• Mean C_max (702 ng/mL) of M1 in the niraparib 200 mg cohort was achieved in a median of 6.0 hours postdose at C1D28 and declined steadily thereafter.
• Results from two patients in the niraparib 300 mg cohort were available; therefore, summary statistics were not calculated (Table: PK Characteristics of Niraparib and Apalutamide When Niraparib was Administered With APA (C1D28): PK-Evaluable Population).
  • At C1D28, C_max values were 842 and 820 ng/mL and AUC_0-24 values were 15,097 and 13,607 ng*h/mL.
  • These values were below or at the lower end of range for the historical monotherapy data (C_max range 582-2230 ng/mL; AUC_0-tau range 14,659-46,900 ng*h/mL) for niraparib in solid tumors suggesting a potential DDI resulting in reduced exposures of niraparib when administered with APA.

PK results of APA and its metabolite M3

• Mean C_max of APA (5.15 µg/mL) in patients who received niraparib 200 mg with APA was achieved in a median of 3.0 hours postdose at C1D28.
• Mean AUC_0-24 was 92.4 µg*h/mL.
• Mean C_max (5.29 µg/mL) of APA metabolite M3 was achieved at 24.0 hours postdose at C1D28.
• PK characteristics of APA and M3 in patients who received niraparib 300 mg with APA were not summarized because data were only available for two patients (Table: PK Characteristics of Niraparib and Apalutamide When Niraparib was Administered With APA (C1D28): PK-Evaluable Population).

Niraparib + AAP group

PK results of niraparib and its metabolite M1

• Niraparib C_max was achieved at a median of approximately 3 hours postdose at cycle 1 day 1 (C1D1) and at 4 hours postdose at C2D1.
• 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_0-24 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_0-24 (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; AUC_0-tau range 14,659-46,900 ng*h/mL) (Table: PK Parameters in Niraparib and Abiraterone When Niraparib 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 C_trough levels of abiraterone at C2D1 were slightly lower for niraparib 300 mg vs 200 mg.
• Summary statistics for abiraterone C_max, 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 two 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.

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 August 2024.