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Asklepios Tumorzentrum Hamburg
Department of Oncology
Dirk Arnold, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Lilly, MSD, Pierre Fabre, and Roche; funds for research support from AstraZeneca, Bristol-Myers Squibb, and Pierre Fabre; fees for non-CME/CE services from Amgen, AstraZeneca, Bristol-Myers Squibb, MSD, Pierre Fabre, and Roche; and other financial or material support from AstraZeneca.
The inhibition of poly-ADP-ribose polymerase (PARP), a key enzyme in the repair of single-stranded DNA breaks, is now an important treatment approach for select patients with pancreatic cancer. The PARP inhibitor olaparib is now approved by both the European Medicines Agency and the FDA for the maintenance treatment of adult patients with metastatic pancreatic adenocarcinoma with germline BRCA mutations whose disease has not progressed on at least 16 weeks of a first-line, platinum-based chemotherapy regimen. These approvals are based on data from the pivotal POLO study.
The POLO trial was a randomized, placebo-controlled, double-blind phase III trial of the PARP inhibitor olaparib vs placebo in patients with metastatic pancreatic cancer and a deleterious/suspected deleterious germline BRCA1/2 mutation (N = 154). Eligible patients had undergone ≥16 weeks of first-line platinum-based therapy (mainly FOLFIRINOX) without progression. Patients were randomized 3:2 to receive olaparib (n = 92) at 300 mg twice daily or placebo (n = 62). The patients continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded independent central review (modified Response Evaluation Criteria in Solid Tumors version 1.1), and secondary endpoints were overall survival (OS), second PFS, objective response rate, and the change in scores of global health-related quality of life.
In the primary analysis of POLO, published in the New England Journal of Medicine, median PFS was significantly improved with olaparib maintenance therapy. Patients receiving maintenance therapy after stable or responding disease to initial platinum-based chemotherapy had a median PFS of 7.4 months compared with 3.8 months for those receiving placebo (HR: 0.53; 95% CI: 0.35-0.82; P = .0038). More recent data, however, presented at American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium 2021 showed that the median OS did not demonstrate a statistically significant between-group difference with an HR of 0.83 (95% CI: 0.56-1.22; P = .3487). The HR improvement of approximately 17% is consistent with the second PFS data, which also showed an improvement, with an HR of 0.66 (95% CI: 0.43-1.02; P = .0613).
What do these data mean, and how do we explain the clinical implications? This trial was not designed to assess OS as the primary endpoint and was inadequately powered to detect a difference in OS between the 2 groups. The patients in the placebo group received multiple subsequent lines of therapies upon progression of disease and after stopping the study medication, which could bias the OS. In addition, even though crossover was not allowed in this study, 15% of patients in the placebo arm received olaparib after disease progression.
The more recent data from the POLO trial demonstrated another interesting finding: a significantly longer time to first subsequent cancer therapy (TFST) or death. Median TFST was 9.0 months in the olaparib arm vs 5.4 months in the placebo arm (HR: 0.44; 95% CI: 0.30-0.66; P <.0001). In addition, there was a larger proportion of patients receiving olaparib who were still alive after 2 years than the placebo group (74% vs 41%, respectively), and a subset of patients receiving olaparib appeared to have long-term OS, even up to 5 years. Olaparib was well tolerated, with an 8.9% rate of discontinuation due to toxicity vs 1.6% in the placebo group. The health-related quality of life (HRQoL) analysis data presented at ASCO 2019 showed that patients’ HRQoL was maintained with maintenance olaparib treatment; however, there was no clinically meaningful difference compared with placebo.
Olaparib maintenance treatment can prolong a patient’s PFS during the beneficial period where disease is well controlled. In the POLO study, the median PFS, when patients have controlled disease, was approximately doubled with maintenance olaparib, suggesting that patients who may be suffering from symptoms of pancreatic cancer before their disease is controlled may benefit from maintaining control of their disease using this treatment approach. For my patients with a germline BRCA mutation, I recommend the use of olaparib as maintenance therapy after a response to platinum-based chemotherapy. Since these updated data, I have also changed my testing strategy and now strongly recommending testing for germline BRCA mutation right from the start of treatment.
In conclusion, despite the lack of statistically significant OS benefit in the POLO study, olaparib offers significantly prolonged PFS. The recently updated data do show the importance of treating patients with germline BRCA metastatic pancreatic cancer with olaparib as maintenance after achieving a response to platinum-based chemotherapy to maintain that response. I am looking forward to seeing longer-term OS follow-up to continue to understand how this treatment approach may affect long-term patient outcomes.
How do you manage your patients with advanced pancreatic cancer? Are you assessing molecular alterations in your patients, and have you employed maintenance therapy? Answer the polling question and join the conversation by posting a comment in the discussion section. Then, check back here for additional information on PARP inhibition in the treatment of patients with pancreatic cancer.