Background: Recent trials in PCa have shown efficacy of PARP inhibitors (PARPi) in patients (pts) with mutations in DDR genes such as BRCA1/2 (TOPARP-B, GALAHAD), as well as efficacy of immunotherapy (IO) in PCa pts with MSI. The combination of PARPi + IO is currently being evaluated in the KEYNOTE-365 trial. This analysis explored the utility of ctDNA in identifying PCa pts who may benefit from PARPi, IO, or a combination. Methods: ctDNA-based comprehensive genomic profiling (Guardant360) of 2,165 PCa pts was performed between 10/2018-08/2019. Frequency of pathogenic somatic BRCA1/2 mutations and MSI are reported. Results: Out of 2,165 PCa pts tested, Guardant360 identified 24 (1.1%) and 59 (2.7%) pts harboring pathogenic somatic BRCA1 or BRCA2 variants, respectively; MSI was detected in 40 (1.8%) PCa pts. Of the 40 MSI samples, 9 (22.5%) pts also had a somatic pathogenic BRCA1 and/or BRCA2 mutation. One pt harbored pathogenic somatic mutations in both BRCA1 and BRCA2. The variant allele frequency (VAF) for somatic pathogenic BRCA1 (N=2) ranged from 0.2-0.88%, and BRCA2 (N=8) ranged from 0.05-12.4%. There were no BRCA1/2 mutations at VAFs suspicious for germline in MSI PCa pts. A median of 19 genomic alterations (range 8-28) was identified among the 9 pts with pathogenic BRCA1/2 variants. The most frequent co-occurring aberrations were found in TP53, APC, AR, BRCA2, ARID1A, PTEN, RB1, and PIK3CA. An 82yo male with recurrent metastatic PCa underwent Guardant360 testing which identified BRCA2 T3085fs at 7.9% VAF and MSI. He was treated with pembrolizumab for 3 cycles and remains in remission. Another 51yo with MSI was treated with pembrolizumab for 4 cycles. He also remains in remission. Subsequent analysis shows clearance of ctDNA and MSI. Conclusions: ctDNA-based comprehensive genomic profiling can be used to detect PCa pts eligible to receive PARPi, IO, or a combination, improving clinical treatment decision making and pt outcomes, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling. PSA and objective responses to IO have been observed in PCa pts with MSI detected by ctDNA.