Genomic and transcriptomic correlates of deep PSA response in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

5089 Background: Despite advances in mHSPC treatment with combination therapies, patient outcomes remain heterogeneous. Achieving an undetectable PSA level is a strong prognostic marker for improved overall survival (OS). Baseline molecular predictors of deep PSA response are lacking. We aimed to identify genomic and transcriptomic determinants associated with undetectable PSA using a large clinical-genomic cohort. Methods: The Tempus Lens Platform was used to query the de-identified Tempus multimodal database and analyze a cohort of patients with mHSPC who underwent DNA (Tempus xT) and RNA (Tempus xR) clinical sequencing. Patients were restricted to those with stage IV disease within 90 days of sample collection. Samples collected within 12 months prior to or within 3 months of androgen deprivation therapy (ADT)-based therapy initiation were considered hormone-sensitive (n = 525). Patients were classified as PSA-low ( < 0.1 ng/mL, n = 285) or PSA-high (≥0.1 ng/mL, n = 240) based on the PSA level at 6 months (±45 days) post-treatment initiation. Genomic alterations, gene expression, and transcriptomic signatures were compared between PSA groups. Real-world OS was defined as the time from ADT start to death or loss to follow-up. Hazard ratios (HR) were estimated using Cox regression and adjusted for age. Significance was calculated using a Wald test at p < 0.05. Results: Median age at diagnosis was 67.5 years; 69.7% were White and 18.5% were Black/African American. The majority (91%) had de novo metastatic disease. First-line treatments included ADT+androgen receptor pathway inhibitor (ARPI) (65% vs 64%), ADT alone (15% vs 18%), ADT+ARPI+docetaxel (19% vs 15%), and ADT+docetaxel (1.3% vs. 3.5%) for PSA-low vs PSA-high, respectively. Baseline PSA was lower in patients with PSA-low vs PSA-high status (median 24 vs 36 ng/mL, p = 0.01). Somatic alterations in SPOP (17% vs 11%, p = 0.04) and ZFHX3 (2.5% vs 6%, p = 0.05) differed between patients with PSA-low and PSA-high, respectively. No significant differences in expression of actionable novel targets including PSMA, TROP2, B7-H3, or STEAP1 were observed between cohorts. Median OS was not reached for patients with PSA-low and was 47 months for patients with PSA-high, with 36-month landmark OS of 83% vs 66%, respectively. On multivariable analysis, PSA-low was independently associated with improved OS (HR 0.51, 95% CI 0.31-0.85, p = 0.01). Conclusions: In a real-world cohort, deep PSA response at 6 months portends significantly improved OS in patients with mHSPC and is associated with more SPOP and fewer ZFHX3 alterations. No transcriptomic differences in emerging therapeutic targets were identified. Validation in independent cohorts is warranted.