PARP1 may predict ICI response in patients with advanced RCC
medwireNews: PARP1 could help identify patients with advanced clear cell renal cell carcinoma (ccRCC) who are likely to benefit from immune checkpoint inhibitor (ICI) treatment, with particular utility in those with PBRM1-mutated disease, indicate findings.
Masayuki Hagiwara (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and co-investigators investigated PARP1 as a potential biomarker because “[s]everal recent studies have shown that the absence of PARP alters the tumor immune microenvironment by inhibiting repair of DNA damage, thereby promoting response to ICI [therapy].”
For the current study, they used genomic and clinical data from 311 participants of clinical trials of PD-1 blockade in the advanced ccRCC setting, 181 of whom received nivolumab, while the remaining 130 received everolimus.
Stratification of nivolumab-treated participants into PARP1-low and high groups, based on the mean z score of messenger RNA expression in the dataset, showed significantly better overall survival (OS) for those with low versus high PARP1 levels, with 3-year OS rates of 53.4% and 31.7%, respectively. And PARP1 status was significantly associated with OS, at a hazard ratio (HR) of 1.70.
However, there was no such significant association between PARP1 status and progression-free survival (PFS) among patients given nivolumab, and no association between PARP1 and either OS or PFS among those treated with everolimus.
The researchers then focused on the 217 participants with available PBRM1 mutation data, explaining that “[d]eleterious PBRM1 mutations are among the most frequent alterations in human cancers, including ccRCC,” and have been linked to ICI treatment response and improved survival.
They found that both OS and PFS were significantly longer among nivolumab-treated patients with low PARP1 levels and PBRM1 mutations than those with either high PARP1 and PBRM1 mutations or with wild-type PBRM1 regardless of PARP1 level.
Once again, there was a significant association between PARP1 status and OS in the subgroup of patients with PBRM1 mutations treated with nivolumab, at an HR of 3.50, and in this case the association was also significant for PFS, at an HR of 2.60.
“[O]ur study suggests that PARP1 can be used as a biomarker to predict response to ICI treatment,” summarize Hagiwara and colleagues in European Urology.
“Furthermore, this work confirms the suitability of combination therapy with [PARP inhibitors plus ICIs] for advanced ccRCC, which is being tested in ongoing clinical trials, and raises the possibility that ccRCC cases with PBRM1 mutation might be good candidates for combination therapy with [a] PARP [inhibitor] and ICI.”
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