Clinico-transcriptomic risk stratification to guide abiraterone treatment intensification in high-risk prostate cancer: A combined analysis of NRG/RTOG 9202, 9413, 9902, and 0521.

5000 Background: Outcomes for some patients with ≥high-risk localized prostate cancer (HR-PCa) who receive radiation therapy (RT) remain poor. Current guidelines recommend intensification with abiraterone/prednisone (AAP) in select patients; however, the current guideline-defined candidate population may be suboptimal. Methods: This is a secondary analysis of available biopsy samples from NRG/RTOG 9202, 9413, 9902, and 0521. The primary objective was to determine if a specific subgroup of ≥HR-PCa patients had sufficiently poor prognoses to derive a clinically meaningful benefit from AAP intensification. The prognostic impact of the Decipher 22-gene genomic classifier (GC; Veracyte, San Diego, CA) was first evaluated for metastasis-free survival (MFS, primary), overall survival (OS), and distant metastases (DM). GC scores were analyzed using both continuous (per 0.1 GC units) and pre-specified categorical cutpoints: ≤ intermediate transcriptomic risk (IR-PCa, GC≤0.6), HR-PCa (GC:0.6-0.85), and very high risk (VHR-PCa, GC > 0.85). A tree-based model was then used to combine clinical and transcriptomic risk category. Results: This study characterized outcomes of 427 patients (64% NCCN HR-PCa; 36% NCCN VHR-PCa) with a median follow-up of 10.4 years. Continuous GC score was observed to discriminate risk when adjusted for age, PSA, grade, T-stage, and treatment received for the endpoints of MFS (HR GC :1.19 [95% CI:1.10-1.29], p < 0.001), DM (HR GC :1.31 [95% CI:1.13-1.51], p < 0.001), and OS (HR GC : 1.18 [95% CI: 1.09-1.28], p < 0.001). MFS and OS were estimated using the Kaplan-Meier method by pre-specified GC subgroup within each NCCN risk group (HR-PCa, VHR-PCa). Based on outcomes by subgroup, a novel clinico-transcriptomic risk stratification system was constructed, where patients receive 1 point for NCCN/GC HR categorization and 2 points for NCCN/GC VHR categorization. The combined risk score ≥3 subgroup had a prognosis similar to the STAMPEDE M0 control arm, whereas the combined score ≤2 subgroup had a substantially better prognosis. Utilizing this system could enhance the specificity of AAP recommendations, increasing the candidate pool eligible for AAP intensification by approximately 20% and identifying approximately 25% of NCCN VHR in whom the therapeutic ratio of AAP may be less favorable. Conclusions: This study defines a novel clinico-transcriptomic risk stratification system to augment current clinical eligibility for AAP intensification. This system may increase the population who benefit from AAP by approximately 20% and simultaneously identify approximately 25% of NCCN VHR patients who may avoid AAP intensification. Acknowledgement: We would like to acknowledge Dr. Felix Feng for his contributions in his capacity as the former GU Committee Chair.