Abstract
PurposeTo 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).MethodsBEDIVERE 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.ResultsThirty-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.ConclusionsThese 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.Trial registration no.NCT02924766 (ClinicalTrials.gov).
Highlights
Recent advances in androgen-receptor-axis-targeted therapies (ARAT) for the treatment of metastatic castrationresistant prostate cancer have led to improved overall survival of up to approximately 35 months in chemotherapy-naive patients and approximately 18 months in patients previously treated with chemotherapy [1,2,3]
Olaparib is approved by the Food and Drug Administration (FDA) for the treatment of adults with metastatic castrationresistant prostate cancer (mCRPC) and deleterious homologous recombination repair (HRR) mutations who progressed after receiving treatment with enzalutamide or abiraterone; recently, rucaparib received accelerated approval for the treatment of adults with mCRPC and deleterious BRCAmutation who previously received ARAT and a taxane-based chemotherapy [13, 14]
dose-limiting toxicities (DLTs) were observed in some patients who received niraparib 300 mg
Summary
Recent advances in androgen-receptor-axis-targeted therapies (ARAT) for the treatment of metastatic castrationresistant prostate cancer (mCRPC) have led to improved overall survival of up to approximately 35 months in chemotherapy-naive patients and approximately 18 months in patients previously treated with chemotherapy [1,2,3]. The PARP inhibitors niraparib, olaparib, and rucaparib are approved by the US Food and Drug Administration (FDA) for the treatment and maintenance treatment of select patients with ovarian, fallopian tube, and primary peritoneal cancers [12,13,14]. Another PARP inhibitor, talazoparib, and olaparib are approved by the FDA for the treatment of select patients with breast cancer [13, 15]. Monotherapy with the PARP inhibitors niraparib, olaparib, rucaparib, and talazoparib has recently been shown to improve clinical outcomes in patients with mCRPC and alterations in HRR genes, BRCA2 [16,17,18,19,20,21]. The results of monotherapy with PARP inhibitors are promising, mCRPC continues to be incurable, and additional drugs and drug combinations are needed to expand the existing treatment armamentarium
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