Germline and somatic mutations in DDR genes have been identified in pancreatic ductal adenocarcinoma (PDAC) [1]. Accordingly, PARP inhibitors are being investigated in a number of settings for HRD-positive pancreatic cancer including their use as maintenance treatment in the first-line setting, as second-line and beyond treatment, and in combination with chemotherapy.
Maintenance treatment first-line
Olaparib maintenance treatment following successful initial treatment with first-line platinum-based chemotherapy has been evaluated in the placebo-controlled phase III POLO trial (NCT02184195) in gBRCA-mutated pancreatic cancer [2]. Patients in the olaparib arm had significantly longer progression-free survival than patients on placebo (7.4 versus 3.8 months, HR 0.53, p = 0.0038). Interim overall-survival data showed no significant difference (18.9 versus 18.1 months; HR 0.91). The objective response rate to olaparib was 23.1% (versus 11.5% in the placebo arm), including 2 enduring complete responses. Interestingly, the duration of response to olaparib in these patients with metastatic pancreatic cancer was 24.9 months. The safety profile was consistent with that seen in other tumours.
Niraparib plus nivolumab or ipilimumab is being evaluated in the phase II PARPVAX trial in patients with advanced pancreatic ductal adenocarcinoma that has not progressed on platinum-based therapy (NCT03404960)[3].
Monotherapy ≥ second line
A number of phase II trials are looking at PARP inhibitors as monotherapy for metastatic pancreatic cancer that has progressed. One such trial is assessing rucaparib as ≥ second-line treatment in patients with a known deleterious BRCA mutation (NCT02042378), and two phase II trials of niraparib as monotherapy are underway in patients with metastatic or unresectable pancreatic cancer that are HRD-positive (NCT03601923, NCT03553004)[4].
Combinations with chemotherapy
Veliparib is being combined with traditional chemotherapy regimens to try to improve outcomes in pancreatic cancer. The main PARP inhibitor combinations being trialled are gemcitabine and cisplatin with or without veliparib versus veliparib in locally advanced or metastatic pancreatic cancer (NCT01585805), veliparib plus the FOLFIRI regimen (irinotecan hydrochloride, leucovorin calcium, fluorouracil) in patients with metastatic pancreatic cancer (NCT02890355), and veliparib plus the FOLFOX regimen (leucovorin, 5-fluorouracil and oxaliplatin) (NCT01489865)[5]. Results from a phase II trial of veliparib plus FOLFOX in patients with metastatic pancreatic cancer reported an ORR of 26%, median progression-free survival of 3.7 months and median overall survival of 8.5 months. Notably, patients who were platinum-naïve, had a family history suggestive of hereditary breast and ovarian cancer syndrome, and a DDR mutation had an ORR of 58%.
References
- Aguirre AJ, Nowak JA, Camarda ND et al. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. Cancer Discov 2018; 8: 1096-1111.
- Golan T, Hammel P, Reni M et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019.
- Reiss KA, Mick R, O'Hara MH et al. A randomized phase II trial of niraparib plus either nivolumab or ipilimumab in patients with advanced pancreatic cancer whose cancer has not progressed on platinum-based therapy. J Clin Oncol 37, 2019 (suppl; abstr TPS4161).
- Kasi A, Chalise P, Williamson SK et al. Niraparib in metastatic pancreatic cancer after previous chemotherapy (NIRA-PANC): A phase 2 trial. J Clin Oncol 37, 2019 (suppl; abstr TPS4168).
- Pishvaian MJ, Wang H, Parenti S et al. Final report of a phase I/II study of veliparib (Vel) in combination with 5-FU and oxaliplatin (FOLFOX) in patients (pts) with metastatic pancreatic cancer (mPDAC). J Clin Oncol 37, 2019 (suppl; abstr 4015).