Genomic characteristics of patients with metastatic hormone-sensitive prostate cancer treated with ARPI-based therapy: A single-center analysis.

244 Background: The addition of androgen receptor pathway inhibitors (ARPI) to androgen deprivation therapy (ADT) has improved survival in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC), both as doublets and as triplets with docetaxel. The prognostic role of genomic alterations (GA) is of growing interest in this setting. We evaluated the GA profiling of a population treated with ARPI-based therapy in a single-center institution. Methods: Our retrospective analysis included patients with mHSPC treated at IRCCS San Raffaele Hospital between 2020 (when ARPI were authorized for mHSPC in Italy) and 2023 (when triplets of ARPI + ADT + docetaxel were authorized). Included patients had a diagnosis of mHSPC, tissue biopsy available for genomic profiling, and were treated with ARPI plus ADT (plus or minus docetaxel) within 120 days of initial diagnosis. Comprehensive genomic profiling (CGP) using a commercial hybrid capture-based system (Foundation Medicine) was performed on all pts to evaluate all classes of GA, homologous recombination score (HRDsig), genomic ancestry, and signature. The log-rank test and Cox proportional hazards models compared GA between responders (Rs: defined as non-progressive pts) and not-responders (NRs: pts developing a progressive disease). Kaplan Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS). Results: 28 patients were included in our analysis. Among them, 25 pts received ARPI + ADT, 3 ARPI + ADT + docetaxel. The median age was 71.8 years (range 53.1-83.9). After a median follow-up of 55.1 months, there were no differences in median PFS (mPFS) between patients treated with triplets and doublets (55.42 vs. 78.0 mos - HR = 1.12; 95%CI, 0.13-9.87; p = 0.92). The median OS (mOS) was not reached in both subgroups, without significant differences in survival rates (HR = 0.32; 95%CI, 0.01-7.33; p = 0.48). The overall response rate was 71.4%, and the disease-control rate was 85.7%. Comparing the CGP profiling between responders and progressive-pts, SPOP mutations were more frequent among Rs than NRs to ARPI (25% vs 0%; p = 0.183). TMPRSS2 - ERG fusions, which tend to be less frequent in SPOP mutated cases, were less frequent in Rs (12.5%) than NRs (20.0% - p = 0.648). There was a similar incidence of other GAs between the two groups of pts, such as PTEN , BRCA1/2 , ATM , and CDK12 (all 12.5% vs. 10.0%; all p > 0.05). Conclusions: In a real-world setting, response to ARPI-based therapy may be associated with characteristic genomic features, such as SPOP mutations, or TMPRSS2 / ERG fusions, both in doublets and in triplet regimens. These findings underscore the importance of larger cohorts to further validate this hypothesis and inspire future research in the treatment selection for mHSPC pts.