Antitumor efficacy of PARP inhibitors in homologous recombination deficient carcinomas

Abstract

PARP inhibitors (PARPis) have remarkable antitumor activity in BRCA mutant ovarian carcinoma. Emerging evidence has shown that responses to PARPis are not limited to BRCA mutant tumors, but could expand to other homologous recombination deficiency (HRD) carcinomas. However, relatively little is known about the efficacy of PARPis in patients with HRD when compared to non‐HRD carriers. In this systematic review, 13 clinical trials were included and analyzed for the treatment effect of PARPis on progression free survival (PFS) and overall survival (OS) for HRD (BRCA mutant HRD, n = 697; BRCA wild‐type HRD, n = 478) vs. non‐HRD (n = 1,417) patients. Pooled analyses of the effect of PARPis in both ovarian and nonovarian carcinoma groups showed significantly higher PFS rates at 6 months and 12 months (PFS6 and PFS12) in the HRD subgroup, as compared to the non‐HRD subgroup. Within the HRD subgroup, the BRCA‐mutant population achieved significantly higher PFS6 (OR: 2.29, 95% CI: 1.03–5.08) and PFS12 (OR: 1.95, 95% CI: 1.26–3.01) when compared to BRCA wild‐type patients. Furthermore, within BRCA wild‐type carcinomas, mutations in other HRD‐related genes also led to increased PFS6 (OR: 1.72, 95% CI: 1.27–2.43) and PFS12 (OR: 1.85, 95% CI: 1.31–2.62), as compared to non‐HRD counterparts. Therefore, patients with HRD carcinomas exhibited pronounced PFS advantages upon treatment with PARPis, as compared to non‐HRD carcinomas. In addition to BRCA mutations, other non‐BRCA HRD‐related aberrations may serve as novel biomarkers for the prediction of PARPi efficacy.

BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining

“…Multiple cancer therapies, such as DNA damage-inflicting irradiation or chemotherapy, are aimed at this vulnerability, however, emerging treatment strategies are aimed to take advantage of disturbed DNA repair systems that may be present in different tumour types. For instance, treatment with PARP inhibitors, which results in increased numbers of doublestrand DNA breaks (DSBs), is clinically effective in carcinomas that are deficient in homologous recombination (HR) 2 , the major error-free pathway that repairs DSBs by predominantly using the sister chromatid as a undamaged template for repair. Careful assessment of the repair capacity of tumour cells can thus influence treatment choice but can also prevent overtreatment, if upfront analysis would predict treatment unresponsiveness.…”

The mechanism of cancer cell death by PARP inhibitors goes beyond DNA damage alone

“…Thus, PARP inhibition, as described by us for CDDP could induce cancer cell apoptosis by ROS‐mediated p53 activation. Consistently with this evidence, as pointed by Yi et al, a phase II clinical trial in gastric cancer showed an increased benefit by PARP inhibitors in patients presenting a functionally compromised ataxia‐telangiectasia mutated protein (ATM) . At this regard, it should be highlighted that ATM not only interferes with DNA repair but also modulates redox stress; in fact, cells lacking wild‐type ATM are prone to ROS accumulation and oxidative stress.…”

“…As reviewed by Yi et al ., clinical evaluation of PARP inhibitors in different trials and settings highlighted the role of mutations in DNA repair mechanisms as a prerequisite for a significant therapeutic efficacy. However, Yi et al .…”

“…As reviewed by Yi et al ., clinical evaluation of PARP inhibitors in different trials and settings highlighted the role of mutations in DNA repair mechanisms as a prerequisite for a significant therapeutic efficacy. However, Yi et al . themselves found that the efficacy of PARP inhibitors, even weaker, is maintained also in the non‐BRCA and non‐HRD cancers, especially in combination regimens.…”

“…Finally, we believe that when discussing the benefit of PARP inhibitor, both in HRD‐ and non‐HRD‐mutated cancer, both if used alone or in combination (i.e., with alkylating agents such as temozolomide), as reviewed by Yi et al ., it should be important to note that these drugs not only affect DNA repair mechanisms in cancer cells, but they also act through different mechanisms (Table ) involving, in particular, the modulation of the energy metabolism, ATP synthesis and oxidative stress, which may contribute to their efficacy and synergism with other drugs. These pleiotropic activities mediated by PARP inhibitors could also provide new approaches for their use in several cancers that are resistant to current therapeutics.…”