Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE).
Aged
Aged, 80 and over
Androstenes
/ therapeutic use
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Humans
Indazoles
/ adverse effects
Male
Middle Aged
Piperidines
/ adverse effects
Poly(ADP-ribose) Polymerase Inhibitors
/ adverse effects
Prednisone
/ therapeutic use
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Receptors, Androgen
/ metabolism
Thiohydantoins
/ therapeutic use
Androgen-signaling-targeted therapy
DRD genes
MCRPC
Niraparib
PARP inhibitors
Pharmacokinetics
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
31
10
2020
accepted:
12
02
2021
pubmed:
24
3
2021
medline:
21
9
2021
entrez:
23
3
2021
Statut:
ppublish
Résumé
To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC). BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer. Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib-apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation. These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib-AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC. NCT02924766 (ClinicalTrials.gov).
Identifiants
pubmed: 33754187
doi: 10.1007/s00280-021-04249-7
pii: 10.1007/s00280-021-04249-7
pmc: PMC8149334
doi:
Substances chimiques
AR protein, human
0
Androstenes
0
Indazoles
0
Piperidines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Receptors, Androgen
0
Thiohydantoins
0
apalutamide
0
abiraterone
G819A456D0
niraparib
HMC2H89N35
Prednisone
VB0R961HZT
Banques de données
ClinicalTrials.gov
['NCT02924766']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
25-37Références
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