1684TiP - PARPiPANC: A multicentric, single arm, phase II assessing niraparib as first line therapy for patients with metastatic homologous repair-deficient pancreatic cancer

Background

PARP inhibitors are active in tumors with defect in homologous DNA repair by a mechanism known as synthetic lethality defined as defects in two or more separate proteins/pathways that induce cell death only when combined. Most studies of PARP inhibitors in pancreatic cancer have shown response rates of 20 to 25% in BRCA1/2 mutation carriers previously exposed to cytotoxic chemotherapy. Since mechanisms of resistance to platinum-based chemotherapy share some similarities with the mechanisms of resistance to PARP inhibitors, we hypothesize that PARP inhibitors may be significantly more active when used in chemotherapy-naïve patients and could represent a chemotherapy-free alternative for pancreatic cancers bearing defects in homologous recombination.

Trial design

This investigator initiated, multicentric, single arm, open-label, phase II aims to assess niraparib in chemotherapy-naïve biomarker-selected pancreatic cancer pts. Only pts with mutation and/or rearrangement, detected locally on tumor or liquid biopsy, leading to inactivation in at least one of the following genes BARD1, BRCA1, BRCA2, BRIP1, FANCA, FANCD2, FANCL, MRE11, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L are eligible. Included pts are treated with niraparib (300mg/d, orally) until loss of clinical benefit, unacceptable toxicity, withdrawal of consent, pt or investigator decision. Primary endpoint is objective response rate after 16 weeks of treatment according to RECIST V1.1 (ORR_16W). Secondary endpoints include duration of response, disease control rate, progression free survival, overall survival and safety. Using a Fleming-A’Hern single stage design with a target ORR_16w of 60% and an inefficacy bound of 30% (α=5% one sided and 90% power) a total of 25 evaluable pts are required. If at least 16 successes (CR or PR at 16 weeks) are observed, niraparib will deserve further investigation. Correlative studies include documentation of HR alteration at time of progression on optional de novo tumor biopsy as well as assessment of predictive value for niraparib resistance of existing or new variants using liquid biopsies. To date, 4 French hospitals are participating.

Clinical trial identification

NCT05442749.

Editorial acknowledgement

Legal entity responsible for the study

Léon Bérard Center.

Funding

GSK.

Disclosure

All authors have declared no conflicts of interest.