Aggressive-variant prostate cancer features and therapeutic outcomes in patients with de-novo metastatic hormone-sensitive prostate cancer.

Abstract

264 Background: Aggressive variant prostate cancer (AVPC) was considered a combination of aggressive phenotypes in metastatic castration-resistant prostate cancer showing poor response to androgen depriving therapy (ADT). However, whether these phenotypes remain predictive and prognostic role in metastatic hormone-sensitive prostate cancer (mHSPC) remained unclear. This study aims to explore the prognostic role of AVPC in de-novo mHSPC. Methods: We retrospectively included 1,167 patients with de-novo metastatic hormone-sensitive prostate cancer (mHSPC) between 2016 and 2025. Patients meeting the clinical criteria of anaplastic prostate cancer at diagnosis or those with AVPC molecular signature (AVPC-MS) (≥2 mutations in TP53, PTEN, and RB1) were identified as AVPC. The main outcomes were castration-resistant free survival (CFS) and overall survival (OS). Univariate and multivariate Cox regression analyses were applied to assess the prognostic role of AVPC in the mHSPC. Results: A total of 208 AVPC were identified. AVPC was associated with poor CFS (median 14.6 vs. 26.8 months, p<0.001) and OS (median 53.7 vs. 76.4 months, p < 0.001) and showed deleterious role in predicting the efficacy of maximal androgen blocking, novel hormone therapy, but not docetaxel plus ADT. Additionally, we found intraductal carcinoma of the prostate, another aggressive pathological variant of prostate cancer not included in the AVPC criteria, was able to stratify patient’ prognosis in patients with AVPC (IDC-P+ vs. IDC-P-: median 11.3 vs. 16.8 months, p=0.0037; OS: 51.5 vs. 54.3 months, p=0.13) and without AVPC (CFS: 20.1 vs. 31.1 months, p<0.001; OS: 60.1 vs. 85.1 months, p<0.001). Multivariate Cox regression analysis confirmed that AVPC and IDC-P independently predicted worse CFS and OS. Conclusions: AVPC predicted worse efficacy of MAB and NHT in de-novo mHSPC. IDC-P could stratify patients with worse prognosis in those with AVPC.