Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•This phase II study was designed to evaluate the benefit of rucaparib among 78 patients with metastatic castration-resistant prostate cancer and non-BRCA DNA damage repair gene alterations. There were responses observed in patients with alterations in PALB2, FANCA, BRIP1, and RAD51B.

•Depending on gene alterations, rucaparib may be of some benefit to patients with metastatic castration-resistant prostate cancer.

– Neil Majithia, MD

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 2 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 1 to 2 lines of next-generation androgen receptor (AR)-directed therapy and 1 taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and prostate-specific antigen (PSA) response (≥50% decrease from baseline).

RESULTS

TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration (ATM [n = 49], CDK12 [n = 15], CHEK2 [n = 12], and other DDR genes [n = 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 (eg, PALB2) may benefit from PARP inhibition.

Clinical Cancer Research

Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase 2 TRITON2 Study

Clin. Cancer Res 2020 Feb 21;[EPub Ahead of Print], W Abida, D Campbell, A Patnaik, JD Shapiro, B Sautois, NJ Vogelzang, EG Voog, AH Bryce, R McDermott, F Ricci, J Rowe, J Zhang, JM Piulats, K Fizazi, AS Merseburger, CS Higano, LE Krieger, CJ Ryan, FY Feng, AD Simmons, A Loehr, D Despain, M Dowson, F Green, SP Watkins, T Golsorkhi, S Chowdhury

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[joeguy]

Interesting...... I have the RAD51C mutation. Wonder if thats close enough ?

[tango65 in reply to joeguy]

RAD51B responds to rucaparib.

clincancerres.aacrjournals....

"Responses were observed in patients with alterations in the DDR genes PALB2,

FANCA, BRIP1, and RAD51B."

[tango65]

Link to the full article:

clincancerres.aacrjournals....

"Responses were observed in patients with alterations in the DDR genes PALB2,

FANCA, BRIP1, and RAD51B."