ASCO 2022: Gene-by-Gene Analysis in the MAGNITUDE Study of Niraparib (NIRA) with Abiraterone Acetate and Prednisone (AAP) in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) and Homologous Recombination Repair (HRR) Gene Alterations.

(UroToday.com) Deployment of PARP inhibitors in prostate cancer has resulted in clear successes for some patients, particularly for those men with alterations in genes with resulting compromise of homologous recombination (HR). Historically, BRCA1 and BRCA2 had the strongest associations with response, yet many other proteins contribute to functional HR. Recently the double-blind, randomized phase III MAGNITUDE study compared the efficacy of the addition of niraparib (versus placebo) to abiraterone acetate and prednisone (AAP) in the treatment of metastatic castration resistant prostate cancer (mCRPC). The study, with data initially presented at the 2022 ASCO Genitourinary Cancers Symposium1, was notable for including two cohorts in both niraparib and placebo arms: those patients with evidence of HR repair alterations (biomarker-positive), defined as qualifying mutation in ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2,and those without (biomarker-negative).

 

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The latter group was stopped for futility after analysis of 223 patients did not show improvement in the composite endpoint of PSA progression or radiographic progression-free survival (HR 1.09, 95% CI 0.75-1.59). In contrast, addition of niraparib to AAP provided the biomarker-positive group a decreased risk of progression or death at a median follow up of 18.6 months. The subset of biomarker-positive patients with either BRCA1 or BRCA2 alterations demonstrated particular benefit in subgroup analyses (e.g. rPFS 16.6 v 10.6 months, HR 0.53, 95% CI 0.36-0.79, p = 0.0014) 

Here, Dr. Sandhu presented analysis of some of the other genes used in MAGNITUDE as putative biomarkers of PARP sensitivity. At a pre-specified analysis of 186 patients with a single alteration in ATM, BRIP1, CDK12, CHEK2, FANCA, HDAC2, or PALB2, 91 in niraparib+AAP and 95 in placebo+AAP. Endpoints included primary endpoint (radiographic progression-free survival [rPFS] by blinded, independent central review), secondary endpoints (time to cytotoxic chemotherapy [TCC], time to symptomatic progression [TSP], overall survival [OS]), as well as time to PSA progression (TPSA) and overall response rate.

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As summarized in the detailed table above, patients with alterations in PALB2 or CHEK2 experienced improvement in all analyzed endpoints. Alterations in ATM conferred benefit in TCC, TSP, TPSA, and ORR. Improvements in TPSA and ORR were observed for the CDK12 subgroup. Given the rarity of some of these alterations, analysis of gene groups was deployed.

The combination of BRIP1, FANCA, and PALB2 into an HRR-Fanconi’s group demonstrated improvement in all endpoints, as when CHEK2 and HDAC2 were grouped.

Taken together, Dr. Sandhu remarks that the overall conclusions of the MAGNITUDE study, namely benefit of addition of niraparib to AAP in mCRPC patients with HR alterations, can be expanded to rarer, less well understood genes contributing to HR. Additional study of these and other genes including their contribution to HR deficiency and associated sensitivity to PARP inhibitors will help allow all patients who may benefit from PARPi will receive them. Additionally, expansion of functional assays and/or genomic classifiers for HRD remains critical for tailoring of these targeted anticancer therapies.

Presented by: Shahneen Sandhu, MD, Ph.D., MBBS, FRACP, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia

Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022. 

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