Interim results of a phase Ib study of niraparib plus androgen receptor-targeted therapy in men with metastatic castration-resistant prostate cancer

Abstract

Background: 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. Methods: 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). Results: 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. Conclusions: 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.