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Table 1 Rationales to combine PARP inhibitors with radical (chemo-)radiotherapy

From: Study protocols of three parallel phase 1 trials combining radical radiotherapy with the PARP inhibitor olaparib

Rationale Locally advanced NSCLC Breast cancer Locally advanced HNSCC
Locoregional recurrence rate despite primary curative (concurrent chemo-) radiotherapy ± 30% after platinum-based CCRT [33,34,35] After combination of systemic treatment, surgery and radiotherapy:
- 19–28% in high risk locally advanced breast cancer [36, 37]
- 20% in inflammatory breast cancer, and up to 38% in triple negative inflammatory breast cancer [38, 39]
± 20–50% after platinum-based or cetuximab based CCRT [40,41,42]
Clinical evidence of benefit of DNA damaging radiosensitisers Absolute benefits of platinum-based CCRT versus SCRT in meta-analysis [33]:
- 5-year OS + 4.5%
- 5-year LR control + 6.1%
N.A. Absolute benefits of CCRT versus RT alone in meta-analysis [43]:
- 5-year OS + 6.5%
- 5-year LR control + 13.5%
for 5-FU/platinum-based CCRT
Indicators of potential tumour specific radiosensitisation
Frequency of HR deficiency - Somatic mutations in BRCA1/BRCA2 (±8%) and ATM genes (±5%) [44, 45] (biomarkers with clinical evidence of PARP inhibitor efficacy in other tumour types [46,47,48,49])
- Alterations in other FA genes (±6%) and other HR genes (±16%) [50] (biomarkers with in vitro evidence of PARP inhibitor efficacy [51, 52])
See Additional file 2: Table S1.
- 5% of all breast cancer patients with germline BRCA 1 or BRCA2 mutations [53] (biomarkers with clinical proof of benefit of olaparib and talazoparib monotherapy in phase 3 double blind randomized control trials [54, 55]
- Up to 20–25% of all breast cancer patients (40–70% in triple negative breast cancer subtype) with HR deficient / BRCA-like tumours# (biomarkers with clinical evidence of benefit of treatment with PARP inhibitors and/or DSB inducing agents#)
See Additional file 2: Table S2.
19–25% of all HNSCC patients with FA/HR gene alterations [50, 56, 57] (biomarkers with in vitro evidence of PARP inhibitor efficacy [51, 52] and limited evidence of clinical benefit of high cumulative cisplatin dose in CCRT [56])
See Additional file 2: Table S3.
Clinical benefit of hypoxia modifying strategies N.A. N.A. In meta-analysis LR control + 8% versus RT alone, with a number needed to treat of 13 [58]
  1. Several biomarkers for homologous recombination deficiency exist with different levels of evidence of PARP inhibitor efficacy. The table lists reported frequencies in order of level of evidence for PARP efficacy. CCRT = concurrent chemoradiotherapy, SCRT Sequential chemoradiotherapy, RT Radiotherapy, OS Overall survival, LR Locoregional, 5-FU 5-fluoro-uracil, HR Homologous recombination, BRCA1 BRCA1, DNA repair associated, BRCA2 BRCA2, DNA repair associated, FA Fanconi anemia, ATM Ataxia telangiectasia mutated, NA Not applicable, # references in Additional file 2: Table S2