Aggressive variants and clinical patterns of progression in real-world metastatic hormone-sensitive prostate cancer (mHSPC).

118 Background: With the evolving treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC), including androgen deprivation therapy (ADT) in combination with androgen receptor pathway inhibitors (ARPI), docetaxel (D) or triplet therapy, understanding the patterns of progression, particularly the emergence of aggressive variants of prostate cancer (AVPC), is increasingly critical. This study investigates the clinical and molecular features at progression and their impact on outcomes. Methods: This is a multicenter retrospective study in mHSPC patients (pts), treated with ADT, ADT + ARPI (abiraterone, enzalutamide or apalutamide), ADT + D or triplet therapy between 2005 and 2025. Baseline clinicopathologic features, follow-up duration, time to progression, and AVPC, defined as at least one of Aparicio criteria (Aparicio, CCR 2016), were assessed at castration-resistant prostate cancer (CRPC). When available, AVPC molecular alterations in PTEN , TP53 or RB1 (AVPCm) determined by next generation sequencing (NGS) were collected. Outcomes included time to CRPC-free survival (CRPC-FS) and overall survival (OS) assessed by Kaplan Meier and the chi-square test was used to assess the association between categorical variables. Results: 442 pts were included: 112 treated with ADT+D, 90 with ADT, 212 with ADT + ARPI and 28 with triplets. Median age was 69,7 years (range 44,2-92,8). 67,5% presented de novo stage IV, 15,4% visceral metastases, 56,8% high volume disease and 50,8% high risk disease. With a median follow-up of 40,8 months (range 3-223), 222 (49,4%) of pts had died and 266 (59,2%) developed CRPC. Among 173 CRPC pts with sufficient clinical data, AVPC were identified in 80 (48,24%) including neuroendocrine differentiation (by biopsy or serum markers) in 9 (5,3%), with 31 (18,2%) of pts presenting >2 criteria. Short time to CRPC was the most common criteria (25,6%). All pts treated with triplet therapy progressed with AVPC. Among AVPC pts with NGS, AVPC-m was present in 10 out of 36 (27,8%). Among pts with baseline mutations in RB1 , PTEN or TP53 , 23 of 48 (47,9%) progressed with AVPC. Pts with high volume disease, visceral metastases and de novo stage IV progressed more frequently with AVPC (p=0.01, p<0.001 and p=0.03 respectively). Median CRPC-FS and OS for the global cohort were 26,2 and 51,7 months respectively. Patients with AVPC had significantly shorter CRPC-FS (26,8 vs 11 months p<0.001) and OS compared to non-AVPC (60,2 vs. 31,7 months, p<0.001). Treatment at progression included ARPI (20,3%), taxane regimen (19,9%), platinum-based regimens (3,4%), or clinical trial enrollment (6,4%). Conclusions: A clinically meaningful proportion of mHSPC pts progress with AVPC, especially those with high volume disease and visceral metastases associated with remarkably poor prognosis. Early recognition and treatment intensification is critical in these pts.