Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities

Table 1 Landmark trials for approved pancreatic ductal adenocarcinoma therapies

Treatment	Tumor characteristic	Primary endpoint	Ref.
Gemcitabine	Advanced PDAC	Median survival, 5.65 mo	Burris et al[3]
Gemcitabine + Erlotinib vs Gemcitabine	Locally Advanced or metastatic PDAC	Overall survival (OS), 6.24 mo vs 5.91 mo	Hoffmann et al[59]
FOLFIRINOX vs Gemcitabine	Metastatic PDAC	OS, 11.1 mo vs 6.8 mo	Conroy et al[4]
Gemcitabine + nab-paclitaxel vs Gemcitabine	Metastatic PDAC	OS, 8.5 mo vs 6.7 mo	Couvelard et al[60]
Gemcitabine + Capacitabine vs Gemcitabine	Resectable PDAC	OS, 28 mo vs 25.5 mo	Neoptolemos et al[8]

PDAC: Pancreatic ductal adenocarcinoma.

Table 2 Pancreatic ductal adenocarcinoma trials involving agents that target tumor metabolism

Drug	Target	Trial description	NCI trial number
IACS-010759	OXPHOS inhibitor	Phase I, in advanced cancers	NCT03291938
CPI-613	PDH/alpha KDH inhibitor	Phase I, combination with Gem + nab-paclitaxel	NCT03435289
CPI-613	PDH/alpha KDH inhibitor	Phase II, combination with FOLFIRINOX	NCT03699319
CPI-613	PDH/alpha KDH inhibitor	Phase III, combination with modified FOLFIRINOX	NCT03504423
Metformin and atorvastatin	Metabolic inhibitors	Metformin + Atorvastatin + Doxycycline + Mebendazole in cancers	NCT02201381
L-glutamine	Glutamine analog	Phase I, combination with Gem + nab-paclitaxel	NCT04634539

OXPHOS: Oxidative phosphorylation; PDH: Pyruvate dehydrogenase; KDH: Ketoglutarate dehydrogenase.

Table 3 Pancreatic ductal adenocarcinoma trials involving agents that target DNA repair

Drug	Target	Trial description	NCI trial number
M6620 (VX-970)	ATR	Phase I, M6620 and irinotecan hydrochloride in treating patients with solid tumors that are metastatic or cannot be removed by surgery	NCT02595931
AZD6738/olaparib	ATR/PARP	Phase II, Phase II trial of AZD6738 alone and in combination with olaparib	NCT03682289
BAY1895344	ATR	Phase I, testing the addition of an anti-cancer drug, BAY 1895344 ATR inhibitor, to the chemotherapy treatment (Gemcitabine) for advanced solid tumors, pancreatic cancer, and ovarian cancer	NCT04616534
Olaparib	PARP	Phase II, a study of pembrolizumab and olaparib for people with metastatic pancreatic ductal adenocarcinoma and homologous recombination deficiency or exceptional treatment response to platinum-based therapy	NCT04666740
Olaparib	PARP	Phase I, targeted PARP or MEK/ERK inhibition in patients with pancreatic cancer	NCT04005690
Olaparib	PARP	Phase II, a phase 2 study of cediranib in combination with olaparib in advanced solid tumors	NCT02498613
Olaparib	PARP	Phase II, olaparib in treating patients with stage IV pancreatic cancer	NCT02677038
Talazoparib	PARP	Phase II, measuring the effects of talazoparib in patients with advanced cancer and DNA repair variations	NCT04550494
Talazoparib	PARP	Phase I/II, a study of avelumab, binimetinib and talazoparib in patients with locally advanced or metastatic RAS-mutant solid tumors	NCT03637491
Niraparib	PARP	Phase II, niraparib in metastatic pancreatic cancer after previous chemotherapy (NIRA-PANC): A phase 2 trial	NCT03553004
Niraparib	PARP	Phase II, niraparib in patients with pancreatic cancer	NCT03601923
Rucaparib	PARP	Phase II, maintenance rucaparib in BRCA1, BRCA2 or PALB2 mutated pancreatic cancer that has not progressed on platinum-based therapy	NCT03140670
MK1775	WEE1	Phase I/II, a phase i and randomized phase II study of nab-paclitaxel/gemcitabine with or without AZD1775 for treatment of metastatic adenocarcinoma of the pancreas	NCT02194829

PARP: Poly (ADP ribose) polymerase.