Promising new inhibitor for prostate cancer with BRCA mutations

Villejuif, 17th february 2023

New England Journal of Medicine
Promising new inhibitor for prostate cancer with BRCA mutations

The international randomized phase III TRITON3 trial evaluated a novel PARP enzyme inhibitor, rucaparib, in patients with metastatic prostate cancer who had BRCA2 alterations and became resistant to hormone therapy. Results showed an increase in progression-free survival of 11.2 months with rucaparib compared to 6.4 months for patients in the physician-choice control arm. This international study coordinated by Prof. Karim Fizazi, a medical oncologist at Gustave Roussy specializing in genitourinary cancers, was presented at the ASCO Genitourinary Cancers Symposium on February 16 and published in the prestigious journal The New England Journal of Medicine.

https://www.nejm.org/doi/full/10.1056/NEJMoa2214676

Nearly 10% of prostate cancer patients have alterations in the BRCA2 gene, either constitutional (all the patient's cells) or tumor-related (only the cancer cells). In both situations, these alterations are a real "Achilles heel" for these cancers, a cellular weakness that partially prevents DNA repair. By using a drug that blocks DNA repair in these individuals, the cancer cells become unable to repair themselves, causing them to become lethargic. Some PARP inhibitors have previously been shown to be clinically effective in BRCA-mutated patients with advanced ovarian, breast, pancreatic and prostate cancer.

TRITON3, an international randomized phase III trial sponsored by Clovis, evaluated the novel PARP inhibitor rucaparib in an earlier setting. It involved men with metastatic prostate cancer that had progressed and become resistant to conventional and second-generation hormone therapy. In order to participate in the study, they had to have an alteration in the BRCA gene (1 or 2) or the ATM gene. Between 2017 and 2022, 4,855 people from 12 countries were selected after tissue or molecular analysis on circulating DNA of their tumor (liquid biopsy). None of these patients had received prior chemotherapy.

Patients were randomized 2:1 between a group treated with rucaparib 600 mg tablets twice daily (270 patients) and a control group of 135 patients in which treatment was left to the physician's choice of either docetaxel chemotherapy or second-generation hormone therapy (abiraterone acetate or enzalutamide).

Results showed that progression-free survival based on imaging, the primary endpoint, was significantly longer with rucaparib compared with the control arm, with medians of 11.2 months versus 6.4 months, respectively, representing a 50% reduction in the risk of progression or death.
Rucaparib was more effective regardless of which drug it was compared to (docetaxel, abiraterone, or enzalutamide). This is the first time a drug has outperformed docetaxel chemotherapy (11.2 months versus 8.3 months, 47% reduction in risk of death or progression). If tumor progression occurred in the control arm, patients could receive rucaparib (crossover).

Overall survival data were not yet mature at the time of publication of these preliminary results, but an interim analysis indicates that the median was 24.3 months with rucaparib versus 20.8 months with physician-selected therapy. The most common adverse events reported with rucaparib were asthenia (anemia-related fatigue) and nausea.
 
"One of the strengths of TRITON3 is that the control arm is based on physician choice, which provides a solid and clinically relevant comparison," said Prof. Karim Fizazi, first author of the study. "The added value of the study also lies in the possibility of crossover from the control arm to rucaparib, ensuring that patients have access to this therapeutic innovation in all cases."

Rucaparib is effective and well-tolerated and is expected to become a standard of care for earlier treatment of patients with metastatic prostate cancer with BRCA2 damage that progresses after dual hormone therapy.

Source :
New England journal of Medicine
Rucaparib versus Physician’s Choice in Metastatic Prostate Cancer
Published 16 february 2023
DOI: 10.1056/NEJMoa2214676

Authors: Karim Fizazi, M.D., Ph.D., Josep M. Piulats, M.D., Ph.D., M. Neil Reaume, M.D., Peter Ostler, M.D., Ray McDermott, M.B., B.Ch., B.A.O., Ph.D., Joel R. Gingerich, M.D., Elias Pintus, M.D., Srikala S. Sridhar, M.D., Richard M. Bambury, M.D., Urban Emmenegger, M.D., Henriette Lindberg, M.D., Ph.D., David Morris, M.D., Franco Nolè, M.D., John Staffurth, M.D., Charles Redfern, M.D., María I. Sáez, M.D., Wassim Abida, M.D., Ph.D., Gedske Daugaard, M.D., D.M.Sc., Axel Heidenreich, M.D., Laurence Krieger, M.D., Brieuc Sautois, M.D., Ph.D., Andrea Loehr, Ph.D., Darrin Despain, M.S., Catherine A. Heyes, B.Sc., Simon P. Watkins, Ph.D., Simon Chowdhury, M.D., Ph.D., Charles J. Ryan, M.D., and Alan H. Bryce, M.D.

Affiliations :
Gustave Roussy Institute, Paris-Saclay University, Villejuif, France (K.F.); Institut Català d’Oncologia – IDIBELL – CiberOnc, Barcelona, Spain (J.P.); The Ottawa Hospital Research Institute, Ottawa, Canada (M.N.R.); Mount Vernon Cancer Centre, Northwood, UK (P.O.); St. Vincent's University Hospital and Cancer Trials Ireland, Dublin, Ireland (R.M.); CancerCare Manitoba, Winnipeg, Canada (J.R.G.); Guy’s Hospital, London, UK (E.P.); Princess Margaret Cancer Centre, Toronto, Ontario, Canada (S.S.S.); Cork University Hospital, Wilton, Cork, Ireland (R.B.); Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (U.E.); Herlev University Hospital, Herlev, Denmark (H.L.); Urology Associates, P.C., Nashville, TN, USA (D.M.); IEO, European Institute of Oncology IRCCS, Milan, Italy (F.N.); Velindre University NHS Trust, Cardiff, UK (J.S.); Sharp HealthCare, San Diego, CA, USA (C.R.); Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga, Spain (M.I.S.); Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA (W.A.); Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (G.D.); Universitätsklinikum Köln, Cologne, Germany and Medical University of Vienna, Vienna, Austria (A.H.); Genesis Care, North Shore, Sydney, Australia (L.K.); University Hospital of Liège, CHU Sart-Tilman, Liège, Belgium (B.S.); Clovis Oncology, Inc., Boulder, CO, USA (A.L., D.D.); Clovis Oncology UK, Ltd, Cambridge, UK (C.A.H., S.P.W.); Guy's Hospital and Sarah Cannon Research Institute, London, UK (S.C.); University of Minnesota, Minneapolis, MN, USA (C.R.); Mayo Clinic, Phoenix, AZ, USA (A.H.B.)