Gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumours: The GCT-SK-004 phase II trial

Mego, Michal; Světlovská, Daniela; Rečková, Mária; Angelis, De; Kalavska, Katarína; Obertová, Jana; Palacka, Patrik; Rejleková, Katarína; Syčová-Milá, Zuzana; Chovanec, Michal; Mardiak, Jozef

doi:10.1007/s10637-021-01130-5

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…Synergistic effects of veliparib and cisplatin or carboplatin were observed only in NTERA-2 CisR cells. However, this combination failed to enhance the cytotoxic effect of cisplatin in vivo , which is in line with the final results of a phase II trial determining the efficacy and toxicity of gemcitabine, carboplatin and veliparib, showing no additive treatment value of veliparib for refractory GCTs ( 32 ). Nevertheless, veliparib still remains valuable agent due to its different mechanism of action in comparison to olaparib and talazoparib, and potential synergistic effect with other treatments.…”

Section: Discussionsupporting

confidence: 67%

“…At the time of the phase II GCT-SK-004 clinical trial initiation and based on the data available, using veliparib in the combination with carboplatin and gemcitabine in multiple relapsed/refractory germ cell tumors seemed to be promising strategy ( 32 ). At the time of study initiation, other PARPi, such as olaparib or talazoparib, were not available, therefore, we analyzed the effect of veliparib also in our cell line models in vitro and in vivo to corroborate the results to those from clinical trial.…”

Section: Discussionmentioning

confidence: 99%

“…Another study showed synergistic cytotoxicity of olaparib and cisplatin against BRCA2-deficient mammary tumor cells ( 24 ). Many clinical trials have been confirmed that the effect of PARP inhibition observed preclinically could be recapitulated in patients ( 25 – 32 ).…”

Section: Introductionmentioning

confidence: 94%

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Effect of the PARP inhibitor veliparib on germ cell tumor cell lines

et al. 2022

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Germ cell tumors (GCTs) usually represent efficiently curable neoplasms due to their chemosensitivity to platinum-based therapeutic regimen. However, some patients develop therapeutic resistance and succumb to their disease. Novel therapeutic approaches are therefore needed for these patients. It has previously been demonstrated that poly (ADP-ribose) polymerase (PARP) expression is upregulated in GCTs compared with normal testis tissue. Therefore, PARP expression was analyzed in GCT cell lines and xenografts and it was examined whether its inhibition by veliparib can reverse cisplatin-resistance. Its expression was analyzed in sensitive and cisplatin-resistant variants (referred to as CisR throughout the manuscript) GCT cell lines and xenografts using quantitative PCR, western blotting and immunohistochemistry. The present study investigated whether the combination of cisplatin with the PARP inhibitor veliparib increased the cytotoxic effect of cisplatin in vitro using a luminescent viability assay and an immunodeficient mouse model in vivo. PARP expression was observed in all tested cell lines, with the highest expression in embryonal carcinoma (EC) cell lines and xenografts. Low or no expression was detected in the JEG-3 choriocarcinoma cell line pairs and xenografts. The combination of veliparib and cisplatin or carboplatin was examined in the cisplatin-resistant NTERA-2 CisR and NCCIT CisR EC cell lines and synergistic effects were observed in NTERA-2 CisR cells. However, in vivo analysis did not confirm this synergy. The present data indicated PARP expression in GCT cell lines and xenografts. However, veliparib failed to increase the cytotoxicity of platinum-based drugs. Therefore, further research is warranted to effectively inhibit PARP using different PARP inhibitors or other drug combinations.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

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Effect of the PARP inhibitor veliparib on germ cell tumor cell lines

et al. 2022

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“…De Giorgi et al (42) reported that olaparib as a single agent showed no objective response in heavily pretreated patients with GCT (n=18), with only 5 patients (27.8%) achieving stable disease. Another clinical trial evaluated veliparib in combination with gemcitabine and carboplatin (n=15), also revealing limited efficacy with 4 partial remissions (26.7%) and 5 cases of disease stabilization (33.3%) (43).…”

Section: Treatmentmentioning

confidence: 99%

Pure testicular choriocarcinoma, a rare and highly malignant subtype with challenging treatment: A case report and review of the literature

Lei,

Wang

et al. 2023

Mol Clin Oncol

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Testicular choriocarcinoma (CC) is the rarest subtype of germ cell tumours (GCTs) of the testis, with a high malignant potential and early haematogenous metastasis. Radical surgical resection should be performed primarily for histological diagnosis, while chemotherapy remains the mainstay of therapy for advanced disease. In the present study, the case of a 65-year-old male patient diagnosed with metastatic testicular CC, who did not fully respond to chemotherapy is reported. This patient underwent surgical removal of the testicular tumour, chemotherapy with etoposide and cisplatin, and radiotherapy of the intracranial lesions. Although the serum human chorionic gonadotropin (HCG) levels of the patient and most of the metastases continued decreasing during chemotherapy, complete response was not achieved after six cycles of chemotherapy. The patient refused high-dose chemotherapy and autologous stem cell transplantation due to severe side effects, and eventually developed respiratory failure on maintenance therapy with oral etoposide. A literature review was then performed, aiming to summarize the characteristics and therapeutic principles of testicular CC. In addition, the emerging therapeutic agents that could be used in maintenance therapy for GCTs, particularly for testicular CC, were also discussed. The limited clinical trials of targeted treatments showed potential benefit for long survival of patients with selected GCTs with fewer side effects. In particular, immunotherapy showed unique potential for testicular CC in preclinical studies, offering new approaches of maintenance therapy for advanced disease. Further studies should shed light on the identification of prognostic factors that predict the response to immune-based therapy in GCTs.

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“…Among PARP inhibitors, olaparib and veliparib in combination with chemotherapy, have been the most investigated. Hematological AEs represented the main toxicities in early phase non-randomized trials, with different incidence and severity according to the safety profile of the chemotherapeutic partner [ 90 , 91 , 92 , 93 , 94 , 95 ]. However, the addition of a PARP inhibitor to chemotherapy inconsistently increased the rate and grade of hematological and non-hematological AEs in randomized studies.…”

Section: Combination Regimensmentioning

confidence: 99%

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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Gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumours: The GCT-SK-004 phase II trial

Cited by 10 publications

References 33 publications

Effect of the PARP inhibitor veliparib on germ cell tumor cell lines

Effect of the PARP inhibitor veliparib on germ cell tumor cell lines

Pure testicular choriocarcinoma, a rare and highly malignant subtype with challenging treatment: A case report and review of the literature

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

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