PARP-inhibitor Olaparib increases progression-free survival in pancreatic patients with inherited mutations, and who have previously had treatment with a platinum based drug.
Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA with limited treatment options and little change in five-year survival over the past decade. With seven per cent of people having inherited mutations, it was only natural to review this cancer for these more treatable factors.
As genetic testing becomes more common, it appears that PDAC is a heterogenous disease, with a group of patients definitely having actionable mutations.
Patients with BRCA1, BRCA2 and others like PALB2, can have a defective repair system for DNA damage. The seven per cent of people can account for 25 percent of pancreatic cancers. In one study of 2818 people with pancreatic cancer (1), BRCA2 mutations were more commonly observed than BRCA1 mutations, BRCA2 mutation was associated with an older age and PALB2 mutation was observed more often in female patients.
The POLO trial (2) demonstrated a significant increase in progression-free survival in metastatic PDAC patients with BRCA1/2 mutations treated with maintenance Olaparib, after previous treatment platinum-based chemotherapy. This was the first phase III randomised trial to establish a genetic approach in the treatment of PDAC.
Other such treatments are under review - EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors Larotrectinib and Entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients (3). Recent clinical trials are studying the effectiveness of PARP inhibitors in combination with immunotherapy, targeted inhibitors, and angiogenesis inhibitors. PARP inhibitors can also work in cases without an inherited mutation and may enhance other drugs in subgroups of patients with PDAC (4).
With seven per cent of the population walking around with inherited mutations and, depending up the cancer, inherited mutations accounting for up to 25% of cancers, it is surely only a matter of time before every patient is offered a BRCA1/2 Test? Hitherto, it was only used for breast and ovarian cancers where the patient had other family members with a similar cancer. Researchers from Southampton actually showed that cancer patients with inherited mutations could live longer than there normal counterparts, in part because of more treatment options.
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References
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Molecular characteristics of BRCA1/2 and PALB2 mutations in pancreatic ductal adenocarcinoma; Andreas Seeber et al; ESMO Open, 2020 Nov;5(6)
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Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer; Hedy L. Kindler et al; J Clin Oncol. 2022 Dec 1;40(34):3929-3939
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Targeting DNA damage repair pathways in pancreas cancer;. Fionnuala Crowley, Wungki Park, Eileen M O'Reilly; Cancer Metastasis Res, 2021 Sep;40(3):891-908
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The role of PARP inhibitors in germline BRCA-associated pancreatic ductal adenocarcinoma; Gordon T Moffat, Eileen M O'Reilly; Clin Adv Hematol Oncol, 2020 Mar;18(3):168-179
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