American Association for Cancer Research
10780432ccr200394-sup-triton2nonbrca_suppfigs3.pdf (125.3 kB)

Suppl Fig S3 from 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

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journal contribution
posted on 2023-03-31, 22:24 authored by 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. Simmons, Andrea Loehr, Darrin Despain, Melanie Dowson, Foad Green, Simon P. Watkins, Tony Golsorkhi, Simon Chowdhury

Supplementary Figure S3. Change in PSA levels over time in patients with an ATM alteration (A), CDK12 alteration (B), CHEK2 alteration (C), or other DDR gene alteration (D). Patients with a PSA response are indicated with closed triangles; patients with a radiographic response are indicated with thicker lines. Abbreviation: PSA, prostate-specific antigen.


Clovis Oncology

Ashfield Healthcare Communications



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. 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). 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. 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.See related commentary by Sokolova et al., p. 2439