PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC).

Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain unclear.

This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes.

Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored.

We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio [HR], 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers.

g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019 Jan 09 [Epub]

Elena Castro, Nuria Romero-Laorden, Angela Del Pozo, Rebeca Lozano, Ana Medina, Javier Puente, Josep Maria Piulats, David Lorente, Maria Isabel Saez, Rafael Morales-Barrera, Enrique Gonzalez-Billalabeitia, Ylenia Cendón, Iciar García-Carbonero, Pablo Borrega, M José Mendez Vidal, Alvaro Montesa, Paz Nombela, Eva Fernández-Parra, Aránzazu Gonzalez Del Alba, José Carlos Villa-Guzmán, Kristina Ibáñez, Alejo Rodriguez-Vida, Lorena Magraner-Pardo, Begoña Perez-Valderrama, Elena Vallespín, Enrique Gallardo, Sergio Vazquez, Colin C Pritchard, Pablo Lapunzina, David Olmos

1 Prostate Cancer Clinical Unit, Spanish National Cancer Research Center, Madrid, Spain., 4 Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, and CIBERER Instituto de Salud Carlos III, Madrid, Spain., 6 Centro Oncológico de Galicia, Coruña, Spain., 7 Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain., 8 Institut Català d'Oncologia, Bellvitge Biomedical Research Institute, Barcelona, Spain., 9 Hospital Universitario La Fe, Valencia, Spain., 5 CNIO_IBIMA Genitourinary Cancer Research Unit, Institute of Biomedical Research in Málaga, Málaga Spain., 11 Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain., 12 Hospital Morales Messeguer-IMIB, UCAM, Murcia, Spain., 14 Hospital Virgen de la Salud, Toledo, Spain., 15 Hospital San Pedro de Alcántara, Cáceres, Spain., 16 Hospital Universitario Reina Sofia, Córdoba, Spain., 17 Hospital Universitario de Valme, Seville, Spain., 18 Hospital Universitario Son Espases, Palma de Mallorca, Spain., 19 Hospital General Universitario de Ciudad Real, Ciudad Real, Spain., 20 Hospital del Mar, Barcelona, Spain., 21 Hospital Universitario Virgen del Rocío, Seville, Spain., 22 Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain., 23 Hospital Universitario Lucus Augusti, Lugo, Spain., 24 University of Washington Medical Center, Seattle, WA.