Antitumor activity of PARPi and POLQi combination therapy in a BRCA-mutated PDAC model

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. BRCA1/2-mutated PDAC is a unique subgroup with exceptional responses to platinum chemotherapy/PARP inhibition (PARPi). A spectrum of responses is observed, from refractory to long term-remission Despite this promising strategy, most patients develop resistance. Inhibition of DNA-polymerase theta (POLQ), a key component in DNA-repair, may further sensitize cancer cells to platinum/PARPi in combination with a PARP1-selective (AZD5305/saruparib) or non-selective PARP inhibitor (olaparib). We conducted a long-term in vivo experiment testing PARPi and POLQi combination utilizing a platinum-sensitive, BRCA2 mutated PDAC PDX model to investigated the potential to prolong response and reduce resistance. Simultaneously, this combination was tested in accordance to the maintenance approach in clinical setting: a cisplatin induction followed by maintenance PARPi, POLQi and their combinations. A total of 159 tumor-bearing mice were randomized to: vehicle control; olaparib; saruparib; POLQi; saruparib+POLQi; olaparib+POLQi, and maintenance treatment groups by cisplatin induction for four weeks followed by switch to: vehicle control; POLQi, saruparib and saruparib+POLQi (n=8-19/group). POLQi alone had no effect on tumor growth. Both PARPi (olaparib/saruparib) monotherapies significantly delayed tumor growth, with saruparib displaying a trend towards prolonged effect vs olaparib (saruparib 69% complete responders (CR) vs control p=0.0014; olaparib 47% CR vs control p=0.0052). Combination therapy of olaparib and POLQi also showed a trend towards extended duration of response compared to olaparib monotherapy (olaparib vs control p=0.005; olaparib+POLQi vs control p=0.00017). Acquired resistance developed in seven mice (22%) with PARPi monotherapy (olaparib n=4, saruparib n=3) and was only seen in five (13%) mice in combination therapy with POLQi (saruparib+POLQi n=3; olaparib+POLQi n=2). In the maintenance study, cisplatin induction initiated a strong anti-tumor effect that was not maintained after switching to vehicle (22% CR by end of study). Addition of saruparib maintenance alone or in combination with POLQi significantly extended the duration of responses (60-70% CR by end of study). Our pre-clinical in vivo data indicate that 1) saruparib displayed a trend towards increased efficacy vs olaparib; 2) combined PARPi and POLQi therapy showed a trend towards extending the duration of response and delaying resistance; 3) cisplatin induction produced a strong antitumor effect which remained with maintenance PARPi±POLQi. Tumors with acquired resistance are undergoing extensive molecular analyses to determine the mechanisms of resistance.This preclinical study enables further understanding and investigation of this unique subtype with the aim to develop alternative treatments to prevent acquisition of resistance.