ESMO 2017: PROREPAIR-B: A prospective cohort study of DNA repair defects in metastatic castration resistant prostate cancer
This study was a prospective, multicenter observational study of 419 newly diagnosed mCRPC patients in Spain (January 2013 - April 2016) with unknown germline mutation status at study entry. Patients were treated at physician-choice’s with either abiraterone, enzalutamide, docetaxel, cabazitaxel or radium-223. The primary endpoint was to assess the impact of BRCA1, BRCA2, ATM and PALB2 germline mutations on cancer-specific survival (CSS) from diagnosis of mCRPC. The study was powered to detect 171 deaths among at least 408 patients to demonstrate a CSS hazard ratio (HR) of germline mutation carriers vs non-carriers equal to 3 (α = 0.05; β = 0.20). Secondary endpoints included the association of these mutations to the response to mCRPC medications. Among these patients, identified germline mutation carriers included: 14 BRCA2, 8 ATM and 4 BRCA1 (6.2%). A non-significant trend to younger age (median 66.5 vs 71.6 years, p = 0.16) was observed in germline mutation carriers compared to non-carriers. Median time from ADT initiation to mCRPC in germline mutation carriers and non-carriers was 23.7 vs 26.7 months (p = 0.22), and 18 months in the BRCA2 subgroup (p = 0.24). Other baseline characteristics were also non-significantly different between germline mutation carriers and non-carriers at first medication initiation: ECOG 0-1 (92% vs 88%), median PSA (27.9 vs 31.0 ng/mL), and bone (96% vs 86%), nodal (48% vs 52%) and visceral (12% vs 16%) metastasis. First medication in germline mutation carriers and non-carriers was a taxane for 63% and 46% of patients respectively, and a novel androgen receptor targeting therapy for 37% and 53%, respectively. After a median follow-up of 36 months, 207 prostate-cancer deaths were observed. Median CSS from mCRPC was 28.5 months in germline mutation carrier group vs 36.0 months in non-carrier group (p = 0.5), and 17.4 months in the BRCA2 subgroup (p = 0.02). Median CSS and progression free survival from first taxane in germline mutation carriers and non-carriers was 17.3 vs 24.5 months, p = 0.6 (BRCA2 12.8 months, p < 0.01) and 7.8 vs 7.1 months, p = 0.4 (BRCA2 5.7 months, p = 0.3), respectively. CSS and PFS from first androgen receptor therapy in germline mutation carriers and non-carriers was 25.4 vs 26.6 months, p = 0.9 (BRCA2 27.6 months, p = 0.05) and 8.2 vs 9.4 months, p = 0.8 (BRCA2 5.8 months, p = 0.4), respectively.
In conclusion, when DNA repair germline mutation carriers were considered, non-significant trends to worse CSS from mCRPC, from first taxane, and from first androgen receptor therapy were observed compared to non-carriers. Furthermore, pre-planned subgroup analyses suggested that BRCA2 mutations are associated with significantly worse outcomes across all treatment regimens.
Speaker: Elena Castro Marcos, Hospital Universitario Quironsalud, Madrid, Spain
Co-Authors: N. Romero Laorden (Madrid, Spain) J. Piulats Rodriguez (Barcelona, Spain) A. Del Pozo (Madrid, Spain) M. Sáez (Malaga, Spain) A. Medina Colmenero (A Coruña, Spain) J. Puente (Madrid, Spain) J. Silla-Castro (Madrid, Spain) R. Lozano Mejorada (Madrid, Spain)
I. Garcia-Carbonero (Toledo, Spain) L. Rivera (Madrid, Spain) M. Mendez Vidal (Cordoba, Spain) R. Morales Barrera (Barcelona, Spain) E. Fernandez Parra (Sevilla, Spain) Y. Cendón Flórez (Madrid, Spain) P. Borrega (Cáceres, Spain) M. Gonzalez Del Alba Baamonde (Palma de Mallorca, Spain) C. Pritchard (Washington, United States of America) P. Lapunzina (Madrid, Spain) D. Olmos Hidalgo (Madrid, Spain)
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain