ASCO 2022: Gene-by-Gene Analysis in the MAGNITUDE Study of Niraparib with Abiraterone Acetate and Prednisone in Patients with mCRPC and HRR Gene Alterations

(UroToday.com) The 2022 ASCO annual meeting featured a session on prostate cancer, including a presentation by Dr. Shahneen Sandhu discussing gene-by-gene analysis in the MAGNITUDE study of niraparib + abiraterone acetate + prednisone in patients with mCRPC and HRR gene alterations. Niraparib + abiraterone acetate + prednisone significantly improved outcomes in patients with mCRPC and HRR gene alterations in the phase 3 MAGNTUDE study. However, there is a paucity of data supporting the use of PARP inhibitors in patients with HRR gene alterations other than BRCA1/2. At ASCO 2022, Dr. Sandhu and colleagues reported on the efficacy of niraparib + abiraterone acetate and prednisone in patients with mCRPC and a  cc other than BRCA1/2.


A pre-specified analysis was undertaken of the primary endpoint (radiographic progression-free survival [rPFS] by BICR), secondary endpoints (time to cytotoxic chemotherapy, time to symptomatic progression, overall survival), as well as time to PSA progression and overall response rate across 186 patients (91 randomized to niraparib + abiraterone acetate + prednisone, and 95 to placebo + abiraterone acetate + prednisone) with an alteration in the ATMBRIP1CDK12CHEK2FANCAHDAC2, or PALB2 gene (excluding co-occurring alterations)The trial design is as follows:

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This analysis of individual alterations was not powered for formal statistical inference. Given the rarity of some alterations, groups based on functional similarity (HRR-Fanconi group [BRIP1, FANCE, PALB2] and HRR-associated group [CHEK2, HDAC2]) are also presented. Double-strand breaks can be detected by different proteins, such as the FANC complex, which recruit HRR effectors including BRCA1, BRCA2, and PALB2:

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Patients with gene alterations in PALB2, CHEK2, and HDAC2 showed benefits across all endpoints, similar to results seen in patients with BRCA1/2 gene alterations. In patients with ATM alterations, the benefit was observed in time to cytotoxic chemotherapy, time to symptomatic progression, time to PSA progression, and overall response rate. There was benefit only in time to PSA progression and overall response rate for patients with CDK12 alterations. When combined into functional groups, patients with an alteration in the HRR-Fanconi pathway (BRIP1FANCA, and PALB2), as well as patients with a HRR associated alteration (CHEK2 or HDAC2), showed improvement in all endpoints. With the exception of CDK12, all individual genes showed improvement in the primary and/or one or more of the secondary endpoints: 

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Dr. Sandhu concluded this presentation by discussing gene-by-gene analysis in the MAGNITUDE study of niraparib + abiraterone acetate + prednisone in patients with mCRPC and HRR gene alterations with the following take-home messages:

  • Clinical benefit was seen in primary, secondary, and other endpoints in patients with HRR gene alterations, both BRCA1/2 and beyond BRCA1/2, who were treated with niraparib + abiraterone acetate + prednisone
  • In addition to improvements in rPFS, improvement in the secondary endpoints, such as delaying time to cytotoxic chemotherapy and prolonging time to symptomatic progression, are particularly relevant for improving the experience of patients with mCRPC
  • These data support the overall conclusions of the MAGNITUDE primary analysis and support the benefit of niraparib + abiraterone acetate + prednisone in patients with HRR gene alterations, both BRCA1/2 and beyond BRCA1/2

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

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md 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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