Real world comparison of time-to-next-treatment (TTNT), time-to-castration-resistance (TTCR), and overall survival (OS) among patients with <i>BRCA1/2</i> positive and homologous recombination repair (HRR) negative metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Heather H. Cheng, Sabree Burbage, Carmine Rossi, Ibrahim Khilfeh, Lilian Diaz, Yuxi Wang, Dominic Pilon, Gordon Andrew Brown, Neal D. Shore, Benjamin H Lowentritt, Daniel W. Lin, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2025)

77 Background: Patients with mCSPC harboring genetic alterations in HRR genes, particularly BRCA1/2 , may experience aggressive disease course and adverse clinical outcomes. This study compared real-world TTNT, TTCR, and OS between patients with BRCA1/2+ and HRR- mCSPC. Methods: Data from oncology centers included in the US-based Flatiron Health-Foundation Medicine, Inc. Metastatic PC Clinico-Genomic Database (1/1/2011–12/31/2022) were evaluated. Patients with mCSPC who received an HRR alteration test and initiated first-line (1L) treatment for mCSPC after 1/1/2018 (index date) were included. Patients with ≥1 positive test for BRCA1/2 ( BRCA1/2 +) and those with no positive test for any HRR alteration (HRR-; 8 alterations) were assessed for TTNT (time from index to start of subsequent treatment for PC), an indicator of clinical/non-clinical performance, TTCR (time from index to prostate-specific antigen increase on therapy or clinician documentation), and OS (time from initial PC diagnosis to death). Baseline characteristics (12 months pre-index) were balanced between cohorts using inverse-probability of treatment weighting. Outcomes between BRCA1/2+ and HRR- patients were compared using weighted Kaplan-Meier analyses. Hazard ratios (HRs), 95% confidence intervals (CIs) and nominal p-values were generated using weighted Cox proportional hazards models. Results: A total of 149 BRCA1/2+ and 1,042 HRR- patients with mCSPC were included. Weighted baseline characteristics were balanced. The median age was 70 years in both cohorts; 60.4% of BRCA1/2+ and 61.2% HRR- patients were White. Abiraterone acetate was most used in 1L ( BRCA1/2 +: 30.2%; HRR-: 30.7%). By 24 months after 1L initiation, a significantly higher proportion of BRCA1/2+ patients progressed to next treatment than HRR- patients (69.7% vs. 56.8%; HR: 1.45 [95% CI: 1.10, 1.92], p=0.009). Median TTNT was shorter in the BRCA1/2+ cohort (10.9 months) than HRR- cohort (18.7 months). By 24 months, a significantly higher proportion of BRCA1/2+ patients progressed to castration resistance than HRR- (72.2% vs. 61.4%; HR: 1.46 [95% CI: 1.16, 1.84], p=0.001). Median TTCR was shorter among the BRCA1/2 + cohort than HRR- cohort (12.9 months vs. 16.9 months). Numerically fewer BRCA1/2+ patients survived 24 months after PC diagnosis (80.6%) than the HRR- cohort (85.4%; HR: 1.46 [95% CI: 0.99, 2.14], p=0.054). Conclusions: This study demonstrates worse outcomes for patients with BRCA1/2+ mCSPC, particularly more rapid treatment changes and progression to mCRPC by 24 months. Given that BRCA1/2 alterations are the most prevalent HRR alterations observed in men with PC, these results support early identification and a need for more effective therapies for this population.