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 = 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 (e.g., PALB2) may benefit from PARP inhibition. See related commentary by Sokolova et al., p. 2439.
|Original language||English (US)|
|Number of pages||10|
|Journal||Clinical Cancer Research|
|State||Published - Jun 1 2020|
Bibliographical noteFunding Information:
TRITON2 was designed by the funder and the first/last authors (W. Abida and S. Chowdhury). This article was written by the authors, with medical writing and copy editing support paid for by the funder. Data were collected by the investigators, analyzed by the funder, and interpreted by all authors. All authors had full access to all trial data and had final responsibility for the decision to submit for publication. Medical writing and editorial support funded by Clovis Oncology were provided by Nathan Yardley and Frederique H. Evans of Ashfield Healthcare Communications. W. Abida is funded by National Cancer Institute (NCI) Cancer Center Support Grant P30 CA 008748, NCI Prostate Specialized Program of Research Excellence (SPORE) grant P50 CA092629-16; Department of Defense Prostate Cancer Research Program grant W81XWH-17-1-0124, and a Prostate Cancer Foundation Young Investigator Award.
© 2020 American Association for Cancer Research.
- DNA Damage
- Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
- Prospective Studies
- Prostatic Neoplasms, Castration-Resistant/drug therapy
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Journal Article
- Research Support, N.I.H., Extramural