Reference Detail

Ref Type

PMID

Authors

Kim N. Chi, Dana E. Rathkopf, Matthew Raymond Smith, Eleni Efstathiou, Gerhardt Attard, David Olmos, Ji Youl Lee, Eric Jay Small, Andrea J. Gomes, Guilhem Roubaud, Marniza Saad, Bogdan Zurawski, Valerii Sakalo, Gary Mason, Adam del Corral, George C. Wang, Daphne Wu, Brooke Diorio, Angela Mennicke Lopez- Gitlitz, Shahneen Kaur Sandhu

Title

Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
J Clin Oncol	40	suppl 6

URL

https://meetinglibrary.asco.org/record/205328/abstract

Abstract Text

Background: Approximately 20% of mCRPC has alterations in genes associated with HRR and is responsive to PARP inhibitors (PARPi) such as NIRA. Combined PARPi with androgen receptor pathway targeting may also benefit unselected mCRPC. MAGNITUDE assessed whether adding NIRA to AAP improves outcomes in pts with mCRPC with or without alterations in HRR associated genes. Methods: MAGNITUDE (NCT03748641) is a randomized, double-blind phase 3 study. In eligible mCRPC pts, =4 mos of prior AAP for mCRPC was allowed. Pts with (HRR biomarker [BM]+; ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR BM-) were randomized 1:1 to receive NIRA 200 mg once daily + AAP or placebo (PBO) + AAP. Primary endpoint was radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in the BRCA1/2 group followed by all HRR BM+ pts. Secondary endpoints were time to initiation of cytotoxic chemotherapy (TTCC), time to symptomatic progression (TTSP) and overall survival (OS). Other endpoints included time to PSA progression (TTPP) and objective response rate (ORR). Results: 423 HRR BM+ pts were randomized to NIRA + AAP (n = 212) or PBO + AAP (n = 211). Median age was 69, 23% had prior AAP, 21% had visceral metastases, and 53% had BRCA1/2 mutations. Median follow-up was 18.6 mos. NIRA + AAP significantly improved rPFS by BICR in the BRCA1/2 subgroup and in all HRR BM+ pts, reducing the risk of progression or death by 47% (16.6 vs 10.9 mo) and 27% (16.5 vs 13.7 mo) respectively (Table), vs PBO + AAP. Investigator assessed rPFS was consistent with BICR. NIRA + AAP delayed TTCC, TTSP, and TTPP and improved ORR in HRR BM+ pts (Table). First interim analysis of OS is immature. The preplanned futility analysis in 233 HRR BM- pts showed no benefit of adding NIRA to AAP in the prespecified composite endpoint (first of PSA progression or rPFS; HR, 1.09; 95% CI, 0.75-1.57). No new safety signals were seen. In HRR BM+ pts, 67% and 46.4% had grade 3/4 AEs and 9% and 3.8% discontinued treatment in the NIRA + AAP and PBO + AAP arms, respectively. There were no clinically significant differences in overall quality of life (FACT-P). Conclusions: NIRA + AAP improves rPFS and other clinically relevant outcomes in pts with mCRPC and alterations in HRR associated genes. There was no evidence of benefit with the addition of NIRA to AAP in HRR BM- pts with mCRPC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References