Niraparib is a potent inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and PARP-2, enzymes involved in DNA repair. PARP-1 is involved in modulating androgen receptor (AR) signaling and function. A phase 1b study (Bedivere) of niraparib + AR-targeted therapy (ART), which combines 1000 mg abiraterone acetate and 10 mg prednisone (AA-P), in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who failed ≥1 line of chemotherapy and ART is ongoing.
The objectives of this multicenter, open-label study were to establish the recommended phase 2 dose (RP2D) of niraparib and to evaluate the safety and pharmacokinetics (PK) of niraparib + ART. A standard 3 + 3 design was used in part 1, followed by niraparib dose expansion in part 2 with the RP2D of niraparib + AA-P. Pts received niraparib 200 or 300 mg once daily + AA-P. Dose-limiting toxicities (DLTs) were evaluated during the first cycle (28 days).
At data cutoff, 16 pts were treated; 12 at 200 mg and 4 at 300 mg niraparib + AA-P. Median age was 62 years (49–81), median PSA was 70.0 ng/mL (2.7–766.9) and median treatment duration was 3.0 months (0.4–6.6). Most pts (11/16) are still on treatment. No DLT was observed with niraparib 200 mg + AA-P. Two pts had grade 4 neutropenia with niraparib 300 mg + AA-P. Niraparib 200 mg + AA-P is selected as the RP2D to be evaluated in part 2. Preliminary PK data (n = 6) suggest the absence of significant interaction between niraparib and AA-P; systemic exposure of the 2 drugs was comparable to that observed with respective monotherapies. At the RP2D (200 mg + AA-P), most common adverse events (AEs) were nausea (5/12, 41.7%), constipation, vomiting, fatigue and back pain (4/12, 33.3% each); serious AEs (SAEs) included nausea and vomiting (1/12, 8.3% each). In the 200 mg cohort, 10 pts (83.3%) had AEs; 1 pt (8.3%) had an SAE. AEs leading to dose interruption/reduction occurred in 3 pts (25%); 2 pts (16.7%) discontinued treatment due to AEs.
Data to date from the Bedivere study support safety and tolerability of a combination of niraparib 200 mg + AA-P in pts with mCRPC. A future phase 3 clinical study will be needed to assess the clinical benefit of the combination in mCRPC pts with DNA repair gene defects.
Clinical trial identification
NCT02924766 First posted: October 5, 2016.
Legal entity responsible for the study
Janssen Research & Development.
Janssen Research & Development.
Medical writing assistance was provided by Tracy T. Cao, PhD of Janssen Global Services, LLC and was funded by Janssen Global Services, LLC.
F. Saad: Honoraria: Astellas, AstraZeneca, Bayer, Janssen, Sanofi; Consulting or advisory role: Astellas, AstraZeneca, Bayer, Janssen, Sanofi; Research funding: Janssen, Astellas, Sanofi, Bayer, AstraZeneca, Bristol-Myers Squibb. K.N. Chi: Honoraria, consulting, advisory role, research funding: Janssen. N. Shore: Research funding: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Clovis, Dendreon, Ferring, GHI, Innocrin, Inovio, Invitae, Merck, Myriad, Janssen, Pfizer, Sanofi-Genzyme; Consulting, advisory role: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Clovis, Dendreon, Ferring, GHI, Innocrin, Inovio, Invitae, Merck, Myriad, Janssen, Pfizer, Sanofi-Genzyme. J.N. Graff: Honoraria, travel, accommodations, expenses: Janssen, Astellas, Sanofi, Bayer; Research funding: Janssen, Astellas, Merck, Sanofi. E.M. Posadas: Consulting, advisory role: Genentech; Speakers' bureau: Bayer; Research funding: Pfizer; Travel, accommodations, expenses: Tracon. S. Freeman: Consulting: Janssen. J. Tryon, J. de Jong, X. Zhao, N. Tran: Employee: Janssen; Stock: Johnson & Johnson. G.C. Trudel: Employee: Janssen; Stock: Johnson & Johnson. J. Meltzer: Employee, contractor: Janssen; Stock: Johnson & Johnson. A. Rezazadeh: Consulting, advisory role: AstraZeneca, Exelixis, Novartis, Pfizer; Speakers' bureau: Janssen, Astellas, Exelixis, Genentech, AstraZeneca, Bristol-Myers Squibb, Novartis, Amgen, Pfizer, Sanofi; Research funding: Janssen, Medivation, Exelixis, Genentech, AstraZeneca, Bristol-Myers Squibb, Bayer, Macrogenics, Eisai, Bioclin, Clovis; Travel, accommodations, expenses: Janssen, Astellas, Exelixis, Genentech, AstraZeneca, Bristol-Myers Squibb, Novarits, Amgen, Pfizer, Sanofi.