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Olaparib as a rescue treatment in platinum-refractory germ-cell tumors: the IGG-02 phase II trial
G Schepisi1, M Urbini2, C Casadei1
1Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy.
Background:
Therapeutic options for patients with advanced germ-cell tumors (GCTs) after multiple relapses or resistant disease are limited. Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA repair.
Patients And Methods:
In this proof-of principle open-label, single-arm, phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ-cell cancer [IGG-02 study (NCT02533765)], patient eligibility included failure after high-dose chemotherapy or after at least two different cisplatin-based regimens.
Results:
Between September 2015 and February 2019, 18 patients, with a median age of 39 years (range 22-61 years) were enrolled. Severe adverse events (AEs) were observed in seven patients. There were no partial responses, five cases (27.8%) with stable disease (SD) lasting 3, 4, 4, 7 and 43 months, and 13 (72.2%) progressive disease. A germline DNA repair profile panel showed only a BRCA1-mutated case associated with an SD lasting for 4 months. The long-lasting patient on olaparib (43 months) experienced a myelodisplastic syndrome (MDS) associated with the onset of a pathogenic mutation affecting PPM1D.
Conclusions:
Olaparib as a single agent demonstrated no activity in heavily pretreated GCT patients. Future studies with PARP inhibitors should be planned in less-pretreated GCT patients based on molecular analysis to support better patient selection.
Insights
Olaparib showed no efficacy in heavily pretreated germ-cell tumor patients. Future PARP inhibitor studies should target less-pretreated patients selected by molecular analysis.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Limited therapeutic options exist for advanced germ-cell tumors (GCTs) post-relapse or resistance.
- Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, targets DNA repair mechanisms.
Purpose of the Study:
- To evaluate the efficacy of olaparib as a single agent in relapsed/refractory metastatic germ-cell cancer patients.
Main Methods:
- An open-label, single-arm, phase II trial (IGG-02 study) administered olaparib 300 mg twice daily.
- Eligibility required failure after high-dose chemotherapy or multiple cisplatin-based regimens.
Main Results:
- No partial responses were observed in 18 heavily pretreated patients.
- Five patients (27.8%) achieved stable disease (SD), with one lasting 43 months.
- Thirteen patients (72.2%) experienced progressive disease; one long-term responder developed myelodysplastic syndrome.
Conclusions:
- Olaparib monotherapy lacks efficacy in heavily pretreated GCT patients.
- Future PARP inhibitor trials should focus on less-pretreated populations identified through molecular profiling.
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