(UroToday.com) The 2026 American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting, held in Chicago, IL, will host the Prostate, Testicular, and Penile Cancer – Posters Session. Dr. Emmanuel S. Antonarakis will present Abstract 5089: Genomic and transcriptomic correlates of deep PSA response in patients with mHSPC.
Despite major advances in combination treatment strategies for metastatic hormone-sensitive prostate cancer (mHSPC), clinical outcomes remain heterogeneous. Achieving an undetectable PSA level after treatment initiation has consistently been associated with improved overall survival, although baseline molecular predictors of deep PSA response remain poorly characterized.
Using the Tempus Lens Platform, the investigators evaluated genomic and transcriptomic determinants associated with achieving an undetectable PSA response in a large real-world clinical-genomic cohort of patients with mHSPC who underwent both DNA and RNA sequencing.
The analysis included 525 patients with hormone-sensitive metastatic disease who underwent clinical sequencing with Tempus xT and Tempus xR. Patients were categorized according to PSA response at 6 months following ADT-based therapy initiation as PSA-low (<0.1 ng/mL; n=285) or PSA-high (≥0.1 ng/mL; n=240).
Baseline characteristics were generally balanced between cohorts. Median age at diagnosis was 67.5 years, 69.7% of patients were White, and 18.5% were Black/African American. Most patients (91%) presented with de novo metastatic disease. First-line treatment patterns were similar between groups, with most patients receiving ADT plus an ARPI.
Baseline PSA levels were significantly lower among patients who ultimately achieved deep PSA responses (median 24 versus 36 ng/mL, p=0.01). Genomic analyses demonstrated that somatic SPOP alterations were more frequent among PSA-low patients compared with PSA-high patients (17% versus 11%, p=0.04), whereas ZFHX3 alterations were more common in PSA-high patients (6% versus 2.5%, p=0.05).
Importantly, no significant transcriptomic differences were observed between cohorts for emerging therapeutic targets, including PSMA, TROP2, B7-H3, or STEAP1.
Clinical outcomes strongly favored patients who achieved deep PSA responses. Median overall survival was not reached among PSA-low patients compared with 47 months in PSA-high patients. The 36-month landmark overall survival rates were 83% versus 66%, respectively. On multivariable analysis adjusted for age, PSA-low status remained independently associated with improved overall survival (HR 0.51, 95% CI 0.31–0.85; p=0.01).
Key Messages:
- Deep PSA response at 6 months was strongly associated with improved overall survival in patients with mHSPC
- Patients achieving PSA <0.1 ng/mL demonstrated significantly improved 36-month overall survival compared with patients with higher PSA levels
- SPOP alterations were enriched among patients achieving deep PSA responses, whereas ZFHX3 alterations were more common in patients with poorer PSA responses
- No significant transcriptomic differences were identified in emerging therapeutic targets such as PSMA, TROP2, B7-H3, or STEAP1
- These findings may help improve molecular prognostication in mHSPC and support further validation in independent cohorts
Presented by: Emmanuel Antonarakis, MD, Clark Endowed Professor of Medicine, Division of Hematology, Oncology and Transplantation, Associate Director of Translational Research, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
Written by: Julian Chavarriaga, MD, Clinical Assistant Professor, Urologic Oncologist, Department of Urology at Penn State Health @chavarriagaj on X during the American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL between May 29th and June 1st, 2026