Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis from the Phase II TRITON2 Study

Wassim Abida, David Campbell, Akash Patnaik, Jeremy D. Shapiro, Brieuc Sautois, Nicholas J. Vogelzang, Eric G. Voog, Alan H. Bryce, Ray McDermott, Francesco Ricci, Julie Rowe, Jingsong Zhang, Josep Maria Piulats, Karim Fizazi, Axel S. Merseburger, Celestia S. Higano, Laurence E. Krieger, Charles J. Ryan, Felix Y. Feng, Andrew D. SimmonsAndrea Loehr, Darrin Despain, Melanie Dowson, Foad Green, Simon P. Watkins, Tony Golsorkhi, Simon Chowdhury

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Purpose: Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. Patients and Methods: TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline). Results: TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration [ATM (n ¼ 49), CDK12 (n ¼ 15), CHEK2 (n ¼ 12), and other DDR genes (n ¼ 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM [2/19 (10.5%) and 2/49 (4.1%), respectively], CDK12 [0/10 (0%) and 1/15 (6.7%), respectively], or CHEK2 [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (e.g., PALB2) may benefit from PARP inhibition.

Original languageEnglish (US)
Pages (from-to)2487-2496
Number of pages10
JournalClinical Cancer Research
Volume26
Issue number11
DOIs
StatePublished - Jun 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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