Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial
Abstract
PARP inhibitors are approved for treating advanced prostate cancers (APC) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B phase II clinical trial samples, evaluating whole-exome and low-pass whole-genome sequencing and IHC and IF assays evaluating ATM and RAD51 foci (testing homologous recombination repair function). BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA2 deletion. Biallelic, but not monoallelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by IHC was associated with a better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alterations while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM IHC expression associated with clinical benefit.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 27, 2021
- Source ID
- 10.1158/2159-8290.cd-21-0007
Entities
People
- Alba Llop-guevara
- Alec Paschalis
- Ana Ferreira
- Bora Gurel
- Chloe Baker
- Christopher J Lord
- Claudia Bertan
- Daniel Nava Rodrigues
- Diletta Bianchini
- Emma Hall
- George Seed
- Ines Figueiredo
- Jan Rekowski
- Jane Goodall
- Joaquin Mateo
- Johann de Bono
- Mateus Crespo
- Nuria Porta
- Pasquale Rescigno
- Rita Pereira
- Ruth Riisnaes
- Sara Arce-gallego
- Stephen J Pettitt
- Susana Miranda
- Suzanne Carreira
- Violeta Serra
- Yuan Wei
Organizations
- Cancer Research UK
- Carlos III Health Institute
- La Caixa
- Prostate Cancer UK
- United States Department of Defense
- Vall d'Hebron Institute of Oncology