Although germline BRCA mutations have been associated with adverse outcomes in prostate cancer (PC), understanding of the association between somatic/germline alterations in homologous recombination repair (HRR) genes and treatment outcomes in metastatic castration-resistant PC (mCRPC) is limited. The aim of this study was to investigate the prevalence and outcomes associated with somatic/germline HRR alterations, particularly BRCA1/2, in patients initiating first-line (1L) mCRPC treatment with androgen receptor signalling inhibitors (ARSi) or taxanes.
Data from 729 mCRPC patients were pooled for CAPTURE from four multicentre observational studies. Eligibility required 1L treatment with ARSi or taxanes, adequate tumour samples and biomarker panel results. Patients underwent paired normal and tumour DNA analyses by next-generation sequencing using a custom gene panel including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B and RAD54L. Patients were divided into subgroups based on somatic/germline alteration(s): with BRCA1/2 mutations (BRCA); with HRR mutations except BRCA1/2 (HRR non-BRCA); and without HRR alterations (non-HRR). Patients without BRCA1/2 mutations were classified as non-BRCA. Radiographic progression-free survival (rPFS), progression-free survival 2 (PFS2) and overall survival (OS) were assessed.
Of 729 patients, 96 (13.2%), 127 (17.4%) and 506 (69.4%) were in the BRCA, HRR non-BRCA and non-HRR subgroups, respectively. BRCA patients performed significantly worse for all outcomes than non-HRR or non-BRCA patients (P < 0.05), while PFS2 and OS were significantly shorter for BRCA than HRR non-BRCA patients (P < 0.05). HRR non-BRCA patients also had significantly worse rPFS, PFS2 and OS than non-HRR patients. Exploratory analyses suggested that for BRCA patients, there were no significant differences in outcomes associated with 1L treatment choice (ARSi or taxanes) or with the somatic/germline origin of the alterations.
Worse outcomes were observed for mCRPC patients in the BRCA subgroup compared with non-BRCA subgroups, either HRR non-BRCA or non-HRR. Despite its heterogeneity, the HRR non-BRCA subgroup presented worse outcomes than the non-HRR subgroup. Screening early for HRR mutations, especially BRCA1/2, is crucial in improving mCRPC patient prognosis.
Annals of oncology : official journal of the European Society for Medical Oncology. 2024 Feb 27 [Epub ahead of print]
D Olmos, D Lorente, D Alameda, C Cattrini, N Romero-Laorden, R Lozano, P P Lopez-Casas, A Jambrina, C Capone, A M Vanden Broecke, M Trevisan, S Van Sanden, A Jürgens, B Herrera-Imbroda, E Castro
Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid. Electronic address: ., Instituto Valenciano de Oncología, Valencia; Hospital Provincial de Castellón, Castellón de la Plana., Instituto de Investigación Biomédica de Málaga, Málaga, Spain., Maggiore della Carità University Hospital, Novara, Italy., Cátedra UAM-Fundación Instituto Roche de Medicina Personalizada de Precisión, Hospital Universitario de La Princesa, Madrid., Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain., Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid., Janssen Inc., Issy-les-Moulineaux, France., Janssen-Cilag B.V., Beerse, Belgium., Janssen Pharmaceuticals, Zug, Switzerland., Janssen Pharmaceutica NV, Beerse, Belgium., Janssen, Neuss, Germany., Instituto de Investigación Biomédica de Málaga, Málaga, Spain; Hospital Universitario Virgen de la Victoria, Málaga, Spain., Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid; Instituto de Investigación Biomédica de Málaga, Málaga, Spain. Electronic address: .