Pancreatic cancer is one of the most difficult cancers to treat, and is still considered incurable. The one-year relative survival rate is 20% and the five-year survival rate is 9%, the lowest of any solid tumour.1 These low rates reflect the fact that more than 80% of tumours have spread beyond the pancreas at the time of diagnosis. For patients diagnosed with metastatic disease, the prognosis is even more bleak, with a five-year survival of only 3%.1 For decades, the only treatment option has been chemotherapy, primarily leucovorin (folinic acid), fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX), but this is a toxic regimen and many patients fail to respond to treatment.2 There is an urgent need for novel therapies for pancreatic cancer that provide efficacy with minimal toxicity.
One of the most eagerly anticipated presentations at the 2019 American Society of Clinical Oncology (ASCO) meeting, which was held on 31 May – 4 June, 2019 in Chicago, Illinois, United States, was the POLO study (NCT02184195). This Phase III study investigated the efficacy and safety of the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib (LynparzaÒ, AstraZeneca) in patients with BRCA-mutated metastatic pancreatic cancer whose disease had not progressed on first line platinum-based chemotherapy. PARP inhibitors act on DNA repair pathways and are particularly effective in tumours with defects in homologous DNA repair, which include tumours associated with mutations in BRCA1 and BRCA2 (BRCA1/2). They have showed promising activity in a number of solid tumours, including breast and ovarian cancer.3,4 Around 5–8% of patients with pancreatic cancer carry a germline BRCA1 or BRCA2 mutation, and these patients have been found to be inherently sensitive to platinum-based chemotherapy.5 However, in patients with advanced disease, prolonged treatment with platinum-based chemotherapy leads to intolerable toxicity and decline in quality of life,2 therefore further treatment options are needed. Early clinical studies have shown that these patients responded to olaparib monotherapy.6
After screening 3,315 patients with metastatic pancreatic cancer who had shown stable disease or partial response during first-line platinum-based chemotherapy, the POLO study investigators identified 247 patients with germline BRCA1 or BRCA2 mutations. Patients in the treatment arm were a median age of 57 years; 58% were male, and 71% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Two-thirds of patients had BRCA2 mutations, and the remainder had BRCA1 mutations. Of the eligible patients, 154 were randomly assigned to receive either olaparib (n=92) or placebo (n=62). The results, which were simultaneously published in the New England Journal of Medicine, showed a 47% improvement in progression-free survival in patients receiving olaparib compared with those receiving placebo (7.4 months versus 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval, 0.35 to 0.82; p=0.004). The overall response rate was 23.1% with olaparib compared with 11.5% in the placebo arm. Two patients treated with olaparib experienced a complete response, both of which were ongoing at data cutoff. Importantly, the median duration of the response to olaparib was high (24.9 months versus 3.7 months for placebo). The safety profile of olaparib was as expected from previous studies;4 Grade 3 or higher adverse events were reported in 40% in the olaparib group and 23% of the placebo group. Adverse events led to treatment discontinuation in 5% and 2% of the patients, respectively. In addition, there was no significant difference between treatment arms in health-related quality of life.7
An interim analysis of overall survival showed no benefit for olaparib, though these data are not yet mature. In addition, despite the fact that the trial did not allow for crossover, 15% of patients in the placebo arm went on to receive a PARP inhibitor following disease progression, which could confound the data. The fact that OS data is not available at 2 years is an impressive outcome in a disease where most people survive for less than a year; at 2 year follow-up, 20% of patients receiving olaparib were still alive and achieving excellent disease control.7
Lead author Hedy L. Kindler, of the University of Chicago Medicine, highlighted the importance of these data, “POLO is the first Phase III randomised study to establish a biomarker-driven approach in the treatment of metastatic pancreatic cancer, and it opens the door to a new era of personalised care for this difficult-to-treat cancer,” she said. “Roughly one in five patients responded to olaparib for a median of 2 years, which is truly remarkable for metastatic pancreatic cancer. For patients with BRCA-driven metastatic pancreatic cancer, we may be seeing a change in patients’ disease trajectory.”8
Since BRCA alterations are inherited, rather than occurring as somatic mutations, it will become important to screen for them in newly diagnosed patients with pancreatic cancer. In January 2019, ASCO issued a provisional clinical opinion (PCO) recommending that all patients diagnosed with pancreatic cancer should undergo risk assessment for hereditary syndromes that increase pancreatic cancer risk. In addition, germline genetic testing for cancer susceptibility, including testing for BRCA mutations, should be discussed with individuals diagnosed with pancreatic cancer, even if family history does not indicate an inheritable syndrome.9
Longer-term data will be needed to assess the full impact of this study. In addition, further studies are needed to identify additional patients who could benefit from this treatment, as the incidence of BRCA mutations in pancreatic cancer is small. The POLO study represents a major step forward in pancreatic cancer therapy, heralding a new era of personalised biomarker-based therapy in this difficult-to-treat disease. First-line platinum-based chemotherapy followed by maintenance with PARP inhibitors is likely to become the new standard of care in metastatic pancreatic cancer patients with platinum-sensitive disease and germline BRCA mutation.
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- Adel N. Current treatment landscape and emerging therapies for pancreatic cancer. Am J Manag Care. 2019;25:S3–S10.
- Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21.
- Konecny GE, Kristeleit RS. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions. Br J Cancer. 2016;115:1157–73.
- Kim R, Byer J, Saif MW. BRCA and pancreatic cancer: selection of chemotherapy. JOP. 2012;13:180–1.
- Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244–50.
- Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Eng J Med. 2019; doi: 10.1056/NEJMoa1903387 [Epub ahead of print].
- von Eyben FE, Roviello G, Kiljunen T, et al. Third-line treatment and (177)Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. Eur J Nucl Med Mol Imaging. 2018;45:496–508.
- Stoffel EM, McKernin SE, Brand R, et al. Evaluating susceptibility to pancreatic cancer: ASCO provisional clinical opinion. J Clin Oncol. 2019;37:153–64.