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A Phase III Randomized, Placebo-Controlled, Double-Blind Study of Niraparib Plus Abiraterone Acetate and Prednisone versus Abiraterone Acetate and Prednisone in Patients with Metastatic Prostate Cancer (MAGNITUDE)

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(UroToday.com) Preclinical data suggest synergistic antitumor activity when the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib is combined with the androgen pathway inhibitor abiraterone acetate. Previously, the addition of PARP inhibitors to abiraterone acetate plus prednisone showed improved radiographic progression-free survival (rPFS) versus abiraterone acetate plus prednisone alone in patients with metastatic castration-resistant prostate cancer (mCRPC) regardless of DNA repair gene defect (DRD) status.1 Interim results from a Phase I study support safety and tolerability of niraparib 200 mg combined with abiraterone acetate plus prednisone in patients with mCRPC.2 MAGNITUDE is a Phase III study comparing the efficacy and safety of niraparib plus abiraterone acetate plus prednisone versus abiraterone acetate plus prednisone with placebo as first-line therapy for mCRPC. At the 2020 American Society of Clinical Oncology Virtual Annual Meeting, Dr. Kim Chi and colleagues discussed the study design of this important trial.

The ongoing multicenter MAGNITUDE study will open in approximately 300 sites across 28 countries and will enroll patients with mCRPC who have not received treatment in the metastatic castrate-resistant setting other than ongoing androgen deprivation therapy (ADT) and ≤ 4 months of abiraterone acetate plus prednisone. DRD status will be determined by plasma and tissue assays. The cohort with DRD (n=400) and the cohort without DRD (n=600) will each be randomized 1:1 to niraparib + abiraterone acetate plus prednisone or placebo + abiraterone acetate plus prednisone. As follows is the study schema for MAGNITUDE:

study schema for MAGNITUDE

Key inclusion criteria for MAGNITUDE include (i) identified DRD status (marker panel: BRCA1, BRCA2, FANCA, PALB2, CHEK2, BRIP1, HDAC2, ATM), (ii) mCRPC, and (iii) score of ≤ 3 on the Brief Pain Inventory-short form question 3 (worst pain in the last 24 hours). The primary objective of the study is to compare rPFS as assessed by blinded independent central radiology review in each cohort and treatment group. To test the superiority of the combination versus abiraterone acetate plus prednisone, sample sizes were estimated to provide 92% power to detect hazard ratio [HR] ≤ 0.65 rPFS in the cohort with DRD and 94% power to detect HR ≤ 0.67 in rPFS in the cohort without DRD, both at a 2-tailed level of significance of 0.05. The secondary objectives are the time to symptomatic progression, time to cytotoxic chemotherapy, and overall survival. Other efficacy endpoints including (i) time to PSA progression by blinded independent central review using PCWG3, (ii) PFS-2 on the first subsequent therapy or death from any cause, (iii) patient-reported outcomes, and (iv) medical resource utilization. Safety and pharmacokinetic profiles will be evaluated.

In conclusion, MAGNITUDE is a Phase III, multi-center, placebo-controlled study that is designed to evaluate the efficacy and safety of niraparib combined with abiraterone acetate plus prednisone versus abiraterone acetate plus prednisone plus placebo as first-line therapy for patients with mCRPC with and without DRD. Patients are currently being recruited with the first patient consented in February 2019.

Clinical trial information: NCT03748641.

Presented by: Kim N. Chi, MD, Senior Research Scientist, Vancouver Prostate Centre, Chief Medical Officer & Vice President, BC Cancer, Medical Oncologist, BC Cancer – Vancouver, Professor, Department of Medicine, University of British Columbia, Vancouver, British Columbia

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020   

References:

1. Clarke, Noel, Pawel Wiechno, Boris Alekseev, Nuria Sala, Robert Jones, Ivo Kocak, Vincenzo Emanuele Chiuri et al. “Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial.” The Lancet Oncology 19, no. 7 (2018): 975-986.

2. Saad, F., K. N. Chi, N. Shore, J. N. Graff, E. M. Posadas, S. Freeman, J. Tryon et al. “Interim results of a phase Ib study of niraparib plus androgen receptor-targeted therapy in men with metastatic castration-resistant prostate cancer.” Annals of Oncology 29 (2018): viii292.

https://www.urotoday.com/conference-highlights/asco-2020/asco-2020-prostate-cancer/121837-asco-2020-a-phase-iii-randomized-placebo-controlled-double-blind-study-of-niraparib-plus-abiraterone-acetate-and-prednisone-versus-abiraterone-acetate-and-prednisone-in-patients-with-metastatic-prostate-cancer-magnitude.html

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