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How I See the Role of PARP Inhibitors Changing in Pancreatic Cancer

Philip Agop Philip, MD, PhD, FRCP

Professor
School of Medicine
Wayne State University
Leader, Gastrointestinal Multidisciplinary Team
Department of Oncology
Karmanos Cancer Institute
Detroit, Michigan


Philip Agop Philip, MD, PhD, FRCP, has disclosed that he has received funds for research support from Astellas, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Corcept, Halozyme, Incyte, Merck, NGM Bio, Novartis, Novocure, QED, Rafeal, Syncore, and Thyme; consulting fees from Blueprint, Erytech, Halozyme, Ipsen, Merck, QED, Rafael, Syncore, and TriSalus; and fees for non-CME/CE services from AstraZeneca, Bayer, Daiichi Sankyo, Incyte, and Novartis.


View ClinicalThoughts from this Author

Released: January 31, 2022

Emerging and Future Roles of PARP Inhibitors in Pancreatic Cancer
Many patients already benefit from the approval of olaparib in the United States and Europe, but there is still room to expand the use of PARP inhibitors (PARPi) in pancreatic cancer. PARPi may be effective in patients with DNA repair mutations other than BRCA1/2, and the combination of PARPi and immunotherapy seems like a promising way to further improve disease control and patient survival. 

Genomic Testing in Pancreatic Cancer
The FDA approved olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test, in which the disease has not progressed in at least 16 weeks of a first-line platinum-based chemotherapy regimen. Current ASCO guidelines recommend germline testing be considered in every patient newly diagnosed with pancreatic cancer. The test is easy to perform as it uses a blood sample and is beneficial not only for treatment purposes but also for risk assessment in the siblings or children of the patient and for determining future surveillance needs. Sometimes, a germline analysis comes via a referral to a genetic counselor who receives the molecular profiling first, so if the information is needed quickly, it is best to order the genetic profiling yourself. Patients with somatic mutations also may benefit from PARPi treatment, so somatic testing also is increasingly being used to detect BRCA1/2-mutated tumors that lack an underlying germline mutation. Testing for somatic mutations is more difficult since it requires a fine‑needle aspiration during an endoscopic ultrasound. Fine-needle aspirations do not always collect enough cells for both diagnostic and genetic testing. Although major academic centers are now using larger needles to obtain more tissue, there is still a need to educate gastroenterologists about procuring sufficient tissue to carry out both diagnostic and molecular testing.

Impact of Genetic Mutations on Treatment Selection
Genetic testing is important even for patients being considered for chemotherapy treatment only. This is because certain chemotherapies such as platinum‑based therapies are more effective in patients with BRCA1/2 and PALB2 mutations. If the patient has a mutation, I select a platinum-based therapy, generally gemcitabine/cisplatin. The patient is very likely to benefit and transition to an oral maintenance treatment. Genomic testing also allows you to better explain your treatment choices to the patient and express your plan for both initial and maintenance therapy. If there are any concerns about giving a certain patient FOLFIRINOX due to tolerability issues, genetic testing would help determine the best alternative therapy. Although the overall incidence of BRCA1/2 mutations is low, it is important to remember that it is enriched in certain patient populations, including patients with Ashkenazi Jewish ancestry. In other cancers, like lung cancer, for instance, some mutations being targeted also are uncommon. Patients with mutations in genes other than BRCA1/2 also may ultimately benefit from PARPi, based on anecdotal reports of patients with other homologous recombination deficiency gene mutations such as PALB2, CDKN2A, ATM, CHEK2, APC, and MUTYH. These mutations are still not well proven, and studies are required to validate these reports.

PARPi as Maintenance Therapy for Locally Advanced Disease
The use of PARPi in metastatic pancreatic cancer is based on data from the pivotal POLO trial. However, patients who have localized disease also may benefit from PARPi maintenance therapy if they are BRCA1/2 or PALB2 mutated. PARPi has the added benefit of being an oral drug that does not require an IV, unlike chemotherapy.

APOLLO is an ongoing phase II trial in the United States comparing olaparib with placebo in patients who have undergone surgical resection or near adjuvant treatment for localized disease followed by surgical resection and chemotherapy. Patients have germline and/or somatic BRCA1/2 mutations and are randomized to receive olaparib or placebo.

Combination Therapies Using PARPi for Metastatic Disease
Although olaparib benefits many patients with germline BRCA1/2 mutations, it does not work in everyone due to resistance mechanisms and mutations that allow tumor cells to resume DNA repair. We can potentially counteract this resistance by using combination therapy with other agents such as immunotherapy.

Future research will help us understand how to use combinations to delay the emergence of PARPi resistance. Other cancers are further ahead in the research of PARPi resistance than pancreatic cancer, so we hopefully will be able to learn how to handle resistance.

Preclinical evidence suggests that combining PARPi with immunotherapy may be additive, if not synergistic. An ongoing randomized trial in the United States is comparing olaparib plus pembrolizumab with olaparib alone in patients with BRCA1/2-mutated metastatic pancreatic cancer who received platinum‑based treatment. Several other trials in the United States also are looking at similar PARPi–immunotherapy combinations.

The addition of chemotherapy to PARPi is another possible mechanism to delay resistance to PARPi and has been tested in a study by Eileen O'Reilly. This study combined gemcitabine, cisplatin with or without veliparib but did not show a benefit for the addition of veliparib. I think this was partly because olaparib added toxicity.

Currently, we do not have enough data to recommend combining PARPi and chemotherapy. Future clinical trials using lower doses of PARPi will be carried out, but I am not very optimistic for these combinations. Platinum-based treatments already improve the antitumor responses in patients with BRCA1/2 mutations, so the addition of a PARPi may not change anything biologically.

Your Thoughts?
Which potential application of PARPi are you most excited about?

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