Inhibition of poly(ADP-ribose) polymerase (PARP), which is part of the single-strand break DNA repair pathway, is synthetic lethal with BRCA1- or BRCA2-induced defects in the homologous recombination (HR) DNA repair pathway. Pharmacological PARP inhibitors (PARPis) have been successfully used in cancers with BRCA mutations, but the number of patients who carry such mutations is small. Two papers have provided insights into how PARPis might be used in some non-BRCA-mutant cancers. Li et al. showed that the androgen receptor (AR) inhibitor enzalutamide, although not usually effective in patients with castration-resistant prostate cancer (CRPC), suppresses expression of several genes associated with HR in CRPC cell lines. This mimics BRCA deficiency, and addition of the PARPi olaparib to CRPC cells after enzalutamide treatment promoted cell death. This treatment combination also inhibited the growth of prostate cancer xenograft tumours in mice. Sun et al. observed that PARPi treatment resulted in upregulation of RAS–MEK–ERK signalling in cancer cells from various tissues and that PARPi-resistant cells also have RAS pathway activation. In these cells, the combination of a PARPi and a MEK inhibitor (MEKi) inhibited cell survival. Interestingly, the authors also found that cancer cells with RAS mutations are resistant to PARPis, and this can be reversed by MEKis both in vitro and in vivo.