Background:Genomic aberrations resulting in homologous recombination repair deficiency (HRD) can be successfully targeted with poly (ADP-ribose) polymerase (PARP) inhibitors. Tumors with HRD also have a higher tumor mutation burden (TMB) and immunogenic phenotypes, prompting PARP inhibitor + immune checkpoint inhibitor (ICI) trials across cancer types. Clear cell renal cell carcinoma (ccRCC) rarely harbors canonical genomic aberrations associated with HRD. However, a “BRCA-like” HRD phenotype can be detected from next-gen DNA- or RNA-sequencing using models trained on tumors with BRCA1/2 bi-allelic loss. We hypothesized that this novel HRD phenotype is associated with ICI benefit in metastatic ccRCC.

Methods:Patients with metastatic ccRCC who underwent nephrectomy and were treated with anti-PD-1/L1 ICI monotherapy +/- ipilimumab were identified in an institutional database (N = 52), and outcomes were determined by chart review. Progression free survival (PFS) and overall survival (OS) were calculated from the start date of ICI treatment. Targeted next generation DNA and whole transcriptome sequencing were performed from archived nephrectomy specimens using the Tempus xT platform. HRD scores were calculated using DNA (HRD-DNA) and RNA (HRD-RNA) based methods as previously described (Liebowitz BD et al. BMC Cancer 2022). HRD status was analyzed as a continuous rather than binary variable, as biologically relevant cutoff thresholds have not been established for ccRCC. Multivariable Cox regression models were used to evaluate the association between HRD scores and PFS or OS when demographic/pathologic covariates were adjusted.

Results:The cohort was predominantly white (n = 48; 92%) and male (n = 37; 71%) with good performance status (ECOG 0-1: n = 47; 90%). Half (n = 26) were current/former smokers; median age 67 years and BMI 28. Twenty-four (46%) nephrectomies were cytoreductive. Most tumors were staged pT3/4 (85%) and grade 3/4 (90%) including 18 (35%) with sarcomatoid histology. ICI monotherapy or ICI + ipilimumab were received by 32 (62%) and 20 (38%) patients, respectively, in the 1st (40%), 2nd (40%), 3rd (17%), or 4th (2%) line. Median PFS and OS for the cohort were 6.4 months (95% CI 4.4-11.1) and 62.7 months (95% CI 32.8-not applicable). HRD-DNA and HRD-RNA could be calculated for 47 and 46 subjects, respectively. HRD-DNA was not found to be associated with PFS nor OS. High HRD-RNA score was associated with improved PFS (HR 0.92 per unit increase; 95% CI 0.85-1.00, p = 0.052) in the multivariable model, but not OS.

Conclusions:High HRD-RNA was associated with longer PFS for metastatic ccRCC patients undergoing ICI-treatment. A “BRCA-like” transcriptomic signature may be predictive of ICI benefit in ccRCC.

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