Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated (HRD) metastatic pancreatic cancer.
Authors: Jazieh Khalid , Babiker Hani M. , Foster Nathan R. , Fruth Briant , Carr Ryan Michael , Alberts Steven R , Conboy Caitlin , Tran Nguyen H. , Hartgers Mindy L. , Halfdanarson Thorvardur Ragnar , Starr Jason S. , Sonbol Mohamad Bassam , Jones Jeremy Clifton , Ahn Daniel H. , Kankeu Fonkoua Lionel Aurelien , Wu Christina , Pedersen Katrina Sophia , Bekaii-Saab Tanios S. , McWilliams Robert R. 
Published: January 2025

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Background:
PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline
BRCA1/2
mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline
BRCA1/2
.
Methods:
We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in
BRCA1/2, PALB2, RAD51C/D,
or
BARD1
. Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials.
Results:
22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was:
BRCA2
13/18 (72%),
BRCA1
4/18 (22%),
BARD1
2/18 (11%). One pt had both
BRCA1
(somatic) and
BRCA2
(germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non-
BRCA2
mutations had a higher DCR12 than those with
BRCA2
mutations (50% vs.17%), with highest DCR12 rates among
BRCA1
patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment.
Conclusions:
PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing.
Clinical trial information: NCT04493060
.