314 - Multi-institutional Transcriptomic Characterization of Radiorecurrent Prostate Cancer and Prognostic Biomarkers after Salvage Re-Irradiation in the F-SHARP Clinical Trial

04:15pm - 04:25pm ET

Room 210

Presenter(s)

Abhishek Solanki, MD, MS - Loyola University Medical Center, Maywood, IL - Illinois

A. A. Solanki¹, J. Proudfoot², W. Adams³, G. Barkan⁴, W. Brisbane⁵, N. B. Desai⁶, A. Farooq⁴, G. Gupta⁷, M. M. Harkenrider¹, E. Kelly⁸, S. Liauw⁹, L. S. Marks⁵, W. Small Jr¹, L. Valle¹⁰, J. B. Weidhaas¹⁰, E. Davicioni², and A. U. Kishan¹⁰; ¹Department of Radiation Oncology, Stritch School of Medicine, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, ²Veracyte, Inc., South San Francisco, CA, ³Biostatistics Core, Clinical Research Office, Loyola University Chicago, Maywood, IL, ⁴Loyola University Medical Center, Maywood, IL, ⁵University of California, Los Angeles, Los Angeles, CA, ⁶University of Texas Southwestern Medical Center, Dallas, TX, ⁷Department of Urology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, ⁸Decipher Urologic Cancers subsidiary of Veracyte, San Diego, CA, United States, ⁹Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, ¹⁰Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

Purpose/Objective(s): Solitary intraprostatic radiorecurrence (IPR) develops in up to one-third of patients with biochemical recurrence after definitive radiotherapy and is increasingly treated with salvage re-irradiation (ReRT). While IPR tumors appear to harbor aggressive molecular features, their prognostic relevance of the salvage ReRT setting is unknown. We compared the transcriptomic landscape of biopsy-confirmed IPR with de novo prostate cancer and evaluated the prognostic significance of genomic biomarkers in the F-SHARP clinical trial.

Materials/Methods: We performed a correlative analysis of F-SHARP, a multi-institutional prospective phase I/II trial of focal salvage HDR for biopsy-confirmed solitary IPR. Transcriptomic profiling of IPR biopsies was performed using the Decipher Prostate Genomic Classifier. These samples were pooled with a retrospectively collected IPR cohort from a second institution and compared with a de novo Gleason Grade Group–matched de novo cohort from the Decipher Genomics Resource for Intelligent Discovery (GRID).

In the F-SHARP cohort, associations between genomic signatures and oncologic outcomes—including biochemical progression-free survival (bPFS), radiographic progression-free survival (rPFS), local recurrence-free survival (LRFS), and metastasis-free survival—were evaluated using Kaplan-Meier and Cox proportional hazards models.

Results: Seventy-two IPR samples (31 F-SHARP; 41 Institution 2) were analyzed and compared with 70,924 matched GRID cases. IPR tumors demonstrated higher median Decipher scores (0.73 vs 0.59) and a greater proportion of high/very-high risk disease (71% vs 48%). IPR tumors were enriched for aggressive biology, including PAM50 basal subtype (56% vs 19%), PSC basal neuroendocrine type (28% vs 6%), neuroendocrine-like signature (17% vs 2%), lower androgen receptor activity (42% vs 7%), p53 mutation (39% vs 23%), and RB loss (10% vs 3%). Rates of homologous recombination deficiency and PTEN loss were similar between groups.

With a median follow-up of 39 months in F-SHARP, higher PORTOS scores were associated with worse bPFS (HR 4.72, p=0.02) and rPFS (HR 5.29, p=0.01). Lower androgen receptor activity was associated with inferior bPFS (HR 0.73, p=0.04), rPFS (HR 0.69, p=0.02), LRFS (0.61, p<0.01). Increasing radiosensitivity index (RSI) was associated with higher risk of grade =2 genitourinary toxicity (HR 1.39 per 0.1 increase, p=0.02).

Conclusion: IPR is enriched for aggressive, AR-attenuated, basal and neuroendocrine-like genomic programs distinct from de novo disease. In F-SHARP, radiation-response and AR-activity signatures were associated with oncologic outcomes, while RSI predicted toxicity risk. These findings suggest that genomic profiling at recurrence may enable risk-adapted Re-RT and treatment intensification. This represents one of the first analyses integrating biopsy-confirmed radiorecurrence biology with prospective ReRT outcomes.