PARP proteins are involved in base excision repair (BER), one of the major DNA repair system in cells. Recently, it was showed that PARP inhibitors have striking efficacy in patients with BRCA1 deficient or triple negative breast cancer in monotherapy or in combination with cisplatin based chemotherapy, without increased systemic toxicity. Pertubations affecting homologous recombination (HR) involved in DNA repair are associated with higher probability of response to PARP inhibitors. Inactivation of PTEN, tumor suppressor protein, is associated with defects in HR and response to PARP inhibitors.~Recently, PARP expression was evaluated in TGCTs. It was showed that PARP is overexpressed in testicular germ cell tumours compared to normal testis and PARP overexpression is early event in TGCTs development. Patients with low PARP expression in primary tumour had non-significantly better OS compared to patients with high PARP expression (5-year OS 89.2% vs 78.7%; HR=0.50, 95% CI 0.21 to 1.17, p=0.12).Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in testicular tumor development, but is associated with progression of disease. Previously, it was showed, that testicular germ cell tumors cell lines have low activity of proteins involved in nuclear excision repair (NER) and it is assumed that low NER activity is related to the favorable response of testis tumors to cisplatin-based chemotherapy.~Gemcitabine and carboplatin showed activity in refractory TGCTs. Recently, maximal tolerated dose of Veliparib (ABT-888) with gemcitabine and carboplatin was established.~Based on aforementioned data, there is strong rationale to inhibit PARP in TGCT. Inactivation of PARP by Veliparib along with defects of homologous recombination due to PTEN inactivation in GCTs and low activity of nucleotide excision repair system will dramatically increase antitumor effect gemcitabine and carboplatin in patients with progressing or relapsing germ cell cancer.
This is a proof-of-concept study to define efficacy of gemcitabine, carboplatin and VELIPARIB (ABT-888) in patients with refractory germ cell tumors (GCTs). PARP proteins are involved in base excision repair (BER), one of the major DNA repair system in cells and PARP is overexpressed in testicular GCTs (TGCTs) compared to normal testis and data suggest that PARP overexpression is early event in TGCTs development. Patients with low PARP expression in primary tumour had non-significantly better OS compared to patients with high PARP expression (5-year OS 89.2% vs 78.7%; HR=0.50, 95% CI 0.21 to 1.17, p=0.12). The aim of this study is to evaluate PARP inhibitor VELIPARIB in combination with gemcitabine, carboplatin in patients with refractory germ cell tumors (GCTs).