Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes and progression to metastatic disease, but no conclusive data are available regarding survival from mCRPC and response to currently approved survival-prolonging therapies (SPT).
Prospective multicentre observational study of newly diagnosed mCRPC patients with unknown germline mutation status at study entry. Patients were treated at physician-choice’s with either abiraterone, enzalutamide, docetaxel, cabazitaxel or Ra-223. Primary endpoint was to assess the impact or BRCA1, BRCA2, ATM and PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. It required enrolling at least 408 patients and to observe at least 171 deaths to demonstrate a CSS HR of germline mutation carriers (C) vs non-carriers (NC) equal to 3 (α = 0.05 & β = 0.20). Secondary endpoints included the association of those mutations to the response to SPT.
From January 2013 to April 2016, 419 eligible patients from 38 Spanish institutions were enrolled. Identified C were 14 BRCA2, 8 ATM and 4 BRCA1 (6.2%). A non-significant (NS) trend to younger age (median 66.5 vs 71.6 yrs, p = 0.16) was observed in C compared to NC. Median time from ADT initiation to mCRPC in C and NC was 23.7 vs 26.7 m (p = 0.22); in the BRCA2 subgroup was 18 m (p = 0.24). Other baseline characteristics were also NS different between C and NC at 1st SPT initiation: ECOG 0-1 (92% vs 88%), median PSA (27.9 vs 31.0), bone (96% vs 86%), nodal (48% vs 52%) and visceral (12% vs 16%) metastasis. 1st SPT in C and NC were a taxane for 63% and 46% for novel AR targeting therapies (ART) for 37% and 53%, respectively. After a median follow-up of 36 m, 207 prostate-cancer deaths were observed. Median CSS from mCRPC was 28.5 m in C vs 36.0 m in NC (p = 0.5), and 17.4 m in the BRCA2 subgroup (p = 0.02). Median CSS and PFS from 1st taxane in C and NC were 17.3 vs 24.5 m, p = 0.6 (BRCA2 12.8 m, p
When all C considered, non-significant trends to worse CSS from mCRPC, from 1st taxane and from 1st ART were observed. Nonetheless, pre-planned subgroup analyses suggest that BRCA2 mutations are associated with significantly worse outcomes.
Clinical trial identification
Legal entity responsible for the study
Spanish National Cancer Research Centre (CNIO) and Instituto de Investigación Biomédica de Málaga (IBIMA)
Prostate Cancer Foundation, Fundación CRIS Contra el Cáncer, Fundación Obra Social La Caixa, Instituto de Salud Carlos III
All authors have declared no conflicts of interest.