Background: 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. Patients and methods: 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. Results: 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. Conclusions: 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.

Currently, there are several options available for the treatment of metastatic castration resistant prostate cancer (mCRPC), however evidence on the optimal treatment sequence is lacking. 223Ra is the first targeted alpha therapy that has shown an improvement in overall survival in mCRPC patients. This drug specifically targets bone lesions, so there is a window of opportunity for the administration of 223Ra previous to the development of visceral metastases. This should be taken into account to design the therapeutic strategy for mCRPC patients. It is necessary, therefore, to review the different approaches in routine clinical practice, to define best practices for patient selection and on-treatment monitoring.

Actualmente las opciones de tratamiento disponibles para el cáncer de próstata resistente a la castración metastásico (CPRCm) son diversas, pero carecemos de datos prospectivos sobre la mejor estrategia de secuenciación en estos pacientes. El dicloruro de 223Ra es el primer radiofármaco emisor de partículas alfa que ha demostrado aumento de supervivencia en pacientes con CPRCm. Este fármaco actúa selectivamente sobre el hueso, por lo que existe una ventana de oportunidad para su administración previa al desarrollo de metástasis viscerales, que debe ser tenida en cuenta a la hora de diseñar la estrategia terapéutica de estos pacientes. Es necesario, por tanto, definir los diferentes escenarios disponibles en la práctica clínica con el fin de llevar a cabo una mejor selección de pacientes y su correcta monitorización.