Background: VHL inactivation may lead to impairments in the DNA damage response pathway and increased replication stress, which consequently can increase the genomic instability of clear cell renal cell carcinoma (RCC). Other molecularly driven RCC subtypes including FH and SDH deficient RCC show impaired DNA repair through oncometabolite accumulation. Synthetic lethality with PARP inhibitors (PARPi) has been suggested in preclinical models, and PARPi may potentiate the effects of immune checkpoint blockade (ICB) therapy. Methods: We conducted a single center, investigator-initiated phase II trial to evaluate combined PARPi + PD-L1 inhibition in two genomically selected advanced RCC cohorts: 1) VHL altered RCC; 2) FH, SDH-RCC and renal medullary carcinoma. For Cohort 1, patients had to have previously been treated with VEGFR TKI and ICB therapy with maximum 3 prior lines of therapy. Patients received talazoparib 1mg daily plus avelumab 800mg IV every 14 days. The primary endpoint was objective response rate (ORR) by iRECIST, and secondary endpoints included progression-free survival (PFS), safety and tolerability. Results from Cohort 1 are reported here. Results: From 2019-2021, 10 advanced RCC patients were enrolled per the first stage of a Simon 2-stage design for cohort 1. The median age was 63 years (R: 42-71), and median number of prior therapies was 2 (R: 1-3). All patients had VHL loss detected by tissue NGS sequencing via MSK-IMPACT, and 3/10 (30%) of patients had co-occurring somatic or germline alterations in DDR specific genes. No objective tumor responses were seen, and the disease control rate was 60% (6/10) with those patients achieving stable disease as best response. All patients experienced disease progression and the median PFS was 3.6 months (95% CI 1.4-4.9). Adverse events were in keeping with reported toxicities for individual agents without emerging safety signals. Conclusions: This is the first clinical study of combination PARPi and ICB therapy in advanced clear cell RCC. In our cohort of VHL deficient TKI/ICB refractory RCC, the study did not meet its pre-defined efficacy threshold to continue enrollment, and our results do not support further study of this regimen in this population. Exploratory efforts to evaluate this treatment approach in other biomarker selected populations of RCC, including cohort 2 of this study, are ongoing. Clinical trial information: NCT04068831.