Outside the maintenance setting, the use of PARPi as single agents has generally underperformed in advanced-stage PC, suggesting that rational combination therapies are necessary in this disease and also relevant to the setting of PARP inhibitor resistance, which has both genomic mechanisms, such as BRCA1 and BRCA2 reversion mutations, and non-genomic mechanisms, including ATR pathway activation in order to bypass the impaired HR-DDR [35,43]. The gene discussed is BRCA1; the disease is pachyonychia congenita.