Abstract A053: Somatic mutations and outcomes of salvage radiation and hormonal therapy for prostate cancer recurrence after prostatectomy

Abstract Purpose/Objectives: Radiotherapy (RT) +/- androgen deprivation therapy (ADT) plays a key role in salvage therapy of prostate cancer (PC) recurrent after radical prostatectomy. However, not all patients benefit, and there is an unmet need for biomarkers to distinguish responders from non-responders (defined as those with second biochemical failure after salvage). We hypothesized that somatic mutations in primary PC are correlated with response to salvage RT+ADT. Materials/Methods: We retrospectively identified 718 consecutive PC patients treated with post-operative RT at a single institution from 1992-2013, of whom 40 were treated with salvage RT+ADT and had formalin-fixed, paraffin-embedded prostatectomy and matched normal tissues available for DNA extraction. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. Whole exome sequencing (WES) was performed to an average depth of 162X (r, 70.7-219). We tested for association between somatic mutations and clinical outcomes using the log-rank test and Cox proportional hazards model. Results: Median age at salvage was 64.5 yrs. High-quality WES data were available in 39 patients. With a median follow-up of 122 months (range, 29-248), 21 experienced second biochemical failure after salvage, while 18 did not. Median time to second biochemical failure was 82.3 months (range, 1.2-140). Overall tumor mutational burden (TMB) was 2.72 mutations/Mb (range, 1.4-12.8). TMB among those with second biochemical failure was 3.9 vs. 3.1 among those without (p=0.29). The most common mutations detected in the overall cohort were PLEC and TTN (n=7). The presence of mutations in BRCA2 (n = 1, p < 0.01, HR = 37 (95% CI: 2.3-600)), CASZ1 (n = 3, p < 0.01, HR = 10 (95% CI: 2.4-44)), XRCC4 (n = 1, p = 0.017, HR = 9.0 (95% CI: 1.0-8.)), ATR (n = 2, p < 0.01, HR = 7.8 (95% CI: 1.6-39)), WDR26 (n = 3, p < 0.01, HR = 6.5 (95% CI: 1.7-24)) and MYT1 (n = 3, p < 0.01, HR = 6.4 (95% CI: 1.5-20)) was significantly correlated with second biochemical failure after salvage RT+ADT. In contrast, none of the patients with mutations in FOXA1 (n=4, p = 0.046, HR: not calculable) experienced second biochemical failure during follow-up. Conclusions: In this cohort of PC patients with >10 years median follow-up after post-prostatectomy salvage RT+ADT, WES revealed that mutations in BRCA2, CASZ1, XRCC4, and ATR were associated with second biochemical failure after salvage therapy, while FOXA1 mutation was associated with favorable outcomes. These findings require validation in larger cohorts, but suggest that somatic mutations may serve as biomarkers to identify patients at greatest risk for recurrence after post-prostatectomy salvage therapy. Citation Format: Keisuke Otani, David J. Konieczkowski, Yukako Otani, Grace Cerrato, Shulin Wu, Philip J. Saylor, Douglas M. Dahl, Chin-Lee Wu, Sophia C. Kamran, Jason A. Efstathiou, David T. Miyamoto. Somatic mutations and outcomes of salvage radiation and hormonal therapy for prostate cancer recurrence after prostatectomy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A053.