Overall survival in veterans with metastatic hormone sensitive prostate cancer by initial therapy and STRATOS-P somatic tumor classification.

5105 Background: The STRATOS-P somatic tumor classification stratifies patients with metastatic hormone-sensitive prostate cancer (mHSPC) into favorable, intermediate, or unfavorable risk groups based on tumor comprehensive genomic profiling (CGP). Currently, no studies have compared the mortality benefits or overall survival (OS) differences between mHSPC treatments in these risk categories. Methods: Veterans within the Veterans Health Administration with mHSPC diagnosed between December 2018 and September 2024 were included if tumor CGP was completed within 6 months of diagnosis. Patients were grouped based on STRATOS-P genomic classification (favorable vs. intermediate/unfavorable). With each group, OS was analyzed by initial therapy: androgen deprivation therapy (ADT) alone, ADT+androgen receptor pathway inhibitor (ARPI), ADT+docetaxel, or triple therapy with ADT+ARPI+docetaxel. Survival was analyzed using Kaplan-Meier and Cox proportional hazards models, adjusting for baseline differences in age, PSA, Charlson comorbidity index, race, and metastatic volume. Results: Of 2,820 veterans with mHSPC, 1,109 (39.3%) had risk classified as favorable per STRATOS-P and 1,711 (60.7%) as intermediate/unfavorable. Initial therapy distribution differed moderately between groups (p=0.046). The favorable group had more patients receiving ADT monotherapy (55.5% vs. 52.0%) and fewer receiving ADT+docetaxel or triple therapy (3.0% vs. 4.7%, 4.4% vs. 5.4%, respectively). The intermediate/unfavorable group had a higher max PSA (median 37.7 vs 23.7, p<0.001) lower percentage of African American patients (27.5% vs 36.0%, p<0.001), and a higher percentage of patients with high volume of disease (28.9% vs. 19.7% p=0.002). In the favorable group, OS did not significantly differ by treatment; however, in a pairwise comparison, ADT+ARPI showed a modest decrease in mortality risk versus ADT alone (aHR [95% CI]: 0.745 [0.561 – 0.989]). In the intermediate/unfavorable group, median OS differed by therapy (ADT monotherapy: 30.7 months, ADT+ARPI: 36.8 months, ADT+docetaxel: 27.9 months, Triple Therapy: 37.6 months; p<0.001). Further, ADT+ARPI and triple therapy were associated with a decreased risk of mortality compared to ADT alone (aHR [95% CI]: 0.638 [0.541 – 0.753], 0.542 [0.360 – 0.817], respectively). Conclusions: In patients with intermediate/unfavorable STRATOS-P genomic risk, choice of initial therapy can lead to differences in OS, with ADT+ARPI and triple therapy associated with decreased mortality compared to ADT alone. In favorable risk, choice of initial therapy had smaller effect on OS, and only ADT+ARPI was associated with a modest decrease in mortality. These findings highlight the role of early genomic testing in mHSPC and that high risk tumors may benefit more from combination therapy than those with favorable risk.