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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Feb 21 [Epub]
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
Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York. ., Medical Oncology, Barwon Health, University Hospital Geelong, Geelong, Victoria, Australia., Hematology and Oncology, University of Chicago Comprehensive Cancer Center, Chicago, Illinois., Medical Oncology, Cabrini Hospital, Malvern, Victoria, Australia., CHU Sart Tilman, University of Liège, Liège, Belgium., Medical Oncology, Comprehensive Cancer Centers of Nevada and US Oncology Research, Las Vegas, Nevada., Medical Oncology, Clinique Victor Hugo Centre Jean Bernard, Le Mans, France., Hematology/Oncology, Mayo Clinic, Phoenix, Arizona., Genito-Urinary Oncology, Adelaide and Meath Hospital (Incorporating the National Children's Hospital), Tallaght, Dublin, Ireland., Department of Drug Development and Innovation (D3i), Institut Curie, Paris, France., Division of Oncology, Department of Internal Medicine, The University of Texas Health Science Center at Houston and Memorial Hermann Cancer Center, Houston, Texas., Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida., Medical Oncology, Institut Català d'Oncologia, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL); ONCOBELL; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC); Hospitalet de Llobregat, Barcelona, Spain., Department of Cancer Medicine, Institut Gustave Roussy, Université Paris-Saclay, Villejuif, France., Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany., Department of Medicine, Division of Oncology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington., Oncology, Northern Cancer Institute, St Leonards, New South Wales, Australia., Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota., Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California., Translational Medicine, Clovis Oncology, Inc., Boulder, Colorado., Biostatistics, Clovis Oncology, Inc., Boulder, Colorado., Study Operations, Clovis Oncology UK, Ltd, Cambridge, United Kingdom., Clinical Science, Clovis Oncology UK, Ltd, Cambridge, United Kingdom., Clinical Development, Clovis Oncology, Inc., Boulder, Colorado., Medical Oncology, Guy's Hospital and Sarah Cannon Research Institute, London, United Kingdom.