Poly(ADP-ribose) polymerase inhibition (PARPi) is an effective therapy for castration-resistant prostate cancer (CRPC) with defects in homologous recombination repair (HRR) genes. However, resistance to PARPi can arise, for example via mutations that restore BRCA function. Reversion mutations in HRR genes can result in PARPi resistance, but these cannot arise in patients with homozygous mutations, possibly explaining why patients with homozygous BRCA2 mutations exhibit more durable responses to PARPi. The mechanisms of resistance in patients with homozygous mutations is unknown and how such mutations occur is not well understood.

A study in Cancer Cell has sought to elucidate these mechanisms, using data from the phase II TOPARP-B trial, which demonstrated antitumour activity of olaparib in patients with metastatic CRPC who had biallelic DNA-damage repair mutations. Notably, the most durable responses were seen in patients with BRCA2 homozygous deletion. These data were also supported by the PROFound trial, which showed reduced radiological progression-free survival (rPFS) in patients with BRCA2 heterozygous mutations compared with those with a homozygous mutation.

聚 （ADP-核糖） 聚合酶抑制 （PARPi） 是治疗同源重组修复 （HRR） 基因缺陷的去势抵抗性前列腺癌 （CRPC） 的有效疗法。然而，可能会出现对 PARPi 的耐药性，例如通过恢复 BRCA 功能的突变。HRR 基因的逆转突变可导致 PARPi 耐药，但这些突变不会出现在纯合突变患者中，这可能解释了为什么纯合 BRCA2 突变的患者对 PARPi 表现出更持久的反应。纯合突变患者的耐药机制尚不清楚，并且这种突变是如何发生的尚不清楚。

Cancer Cell 上的一项研究试图使用 II 期 TOPARP-B 试验的数据来阐明这些机制，该试验证明了奥拉帕尼在具有双等位基因 DNA 损伤修复突变的转移性 CRPC 患者中的抗肿瘤活性。值得注意的是，在 BRCA2 纯合缺失患者中观察到最持久的反应。这些数据也得到了 PROFound 试验的支持，该试验显示，与纯合突变患者相比，BRCA2 杂合突变患者的放射学无进展生存期 （rPFS） 降低。