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Targeting an Important Tumor Vulnerability With Maintenance Olaparib in Germline BRCA-Mutated Pancreatic Cancer


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In the POLO trial, which is discussed in this issue of The ASCO Post, Golan and colleagues evaluated the potential benefit of maintenance olaparib after disease stability or response to a minimum of 4 months of platinum-based chemotherapy in patients with metastatic pancreatic cancer and a pathogenic germline mutation in BRCA1 or BRCA2.1 Patients with advanced pancreatic cancer currently have limited treatment options, and median survival times remain less than 12 months using available chemotherapy regimens.2,3

Brian M. Wolpin, MD, MPH

Brian M. Wolpin, MD, MPH

Multiple studies have now probed the germline and somatic DNA mutations present in patients with pancreatic cancer.4-10 In studies of patients unselected by age or family history, 3% to 6% have been identified to carry a germline inactivating mutation in BRCA1 or BRCA2. These genes encode for proteins that participate in homologous recombination repair of DNA double-strand breaks. When cells lack functional BRCA1 or BRCA2, they become sensitive to growth inhibition by platinum drugs and poly (ADP ribose) polymerase (PARP) inhibitors such as olaparib.

Several PARP inhibitors are now approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of patients with breast and ovarian cancers, where pathogenic BRCA1 and BRCA2 mutations are also common.11 Small studies in pancreatic cancer have suggested clinical activity of PARP inhibitors in patients with BRCA1 or BRCA2 inactivating mutations,12-14 leading to the larger study conducted by Golan and colleagues.

POLO Trial: Key Findings

In the reported study,1 3,315 patients underwent germline DNA sequencing to identify 247 (7.5%) who carried a pathogenic mutation in BRCA1 or BRCA2. Of these 247 patients, approximately 20% were already known to carry the mutation from local testing, such that in the true screening population, the prevalence of BRCA mutations was 6%—within the prevalence range identified in prior studies. Of those with a germline mutation, 154 underwent 3:2 randomization to olaparib vs placebo after demonstrating disease control (stable disease, partial response, or complete response) for at least 4 months on platinum-based first-line chemotherapy.

The patients who received olaparib had longer median progression-free survival compared with those who received placebo (7.4 vs 3.8 months, hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.35–0.82, P =.004). Additionally, the response rate was higher in the olaparib arm than in the placebo group (23% vs 12%), with durable responses observed for those patients receiving olaparib (median duration of response = 24.9 vs 3.7 months). Although evaluated at a planned interim analysis with just 46% data maturity, overall survival did not significantly differ between the two groups (HR = 0.91, 95% CI = 0.56–1.46, P =.68).

Foothold for Targeted Therapy in Pancreatic Cancer

The results of the POLO trial provide an important foothold for targeted therapy in pancreatic cancer, while also highlighting the need for further work to improve upon these results and expand the patient population who may benefit from targeting DNA damage repair pathways. Notably, few prior studies in metastatic pancreatic cancer have demonstrated a doubling of median progression-free survival with an experimental agent. The nearly 25% of patients who had a Response Evaluation Criteria in Solid Tumors (RECIST)-defined response to olaparib continued to respond for a median of over 2 years—a timeframe of response uncommon in this disease.

It is important to note that the efficacy of olaparib was seen whether patients had stable disease or a partial or complete response to prior platinum-based chemotherapy and whether patients received 4 to 6 months or more than 6 months of prior chemotherapy. Thus, longer chemotherapy exposure and lack of major response to platinum-based chemotherapy do not appear to be barriers to benefit from maintenance olaparib.

The lack of overall survival benefit is somewhat disappointing, but data for the overall survival endpoint are not mature.
— Brian M. Wolpin, MD, MPH

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Nevertheless, many oncologists treating patients with the standard chemotherapy program of FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin) use a scaled-back version of this regimen (such as 5-FU/leucovorin, with or without irinotecan) after 4 to 6 months due in part to neurotoxicity from oxaliplatin, and the current study does not demonstrate whether PARP inhibition is superior to this strategy, just to placebo. Interestingly, almost 10% of patients who received placebo were progression-free at 2 years, showing the activity of platinum-based chemotherapy in patients with BRCA1 or BRCA2 mutations and providing additional support for the universal germline testing now recommended in the National Comprehensive Cancer Network Clinical Practice Guidelines and ASCO consensus guidelines.15,16

Lastly, the lack of overall survival benefit is somewhat disappointing, as progression-free survival benefit commonly predicts overall survival benefit in cancers with few treatment options. Nevertheless, data for the overall survival endpoint are not mature, and higher rates of both PARP inhibitor and platinum chemotherapy use after discontinuation of study treatment were noted in the placebo arm, which may obscure overall survival differences.

‘Targetable’ Alterations and Next Steps

DNA-sequencing studies in pancreatic cancer suggest that more than one-third of patients have a theoretically “targetable” alteration, whether that be mutation, copy number change, translocation, or other alteration.7,8,17 For two of these alterations—mismatch repair deficiency and NTRK fusion—tumor-agnostic FDA approvals now provide treatment options for 1% to 2% of patients with pancreatic cancer.18,19 However, impaired DNA damage repair is identified in up to 25% of pancreatic cancers when other genes are considered beyond BRCA1 and BRCA2, such as ATM, CHEK2, PALB2, RAD51C, and others.

The field has several clear next steps to build upon the important results of the POLO trial: (1) determine why some patients with germline BRCA1 or BRCA2 mutations benefit from PARP inhibition and others do not; (2) identify combination partners to administer with PARP inhibitors to improve outcomes in patients with germline BRCA1 or BRCA2 mutations; (3) evaluate inhibitors of PARP and other DNA damage repair proteins in patients with somatic mutations in BRCA1 or BRCA2 and in patients with germline or somatic mutations in other DNA damage repair genes; and (4) characterize new assays that can identify patients likely to benefit from DNA damage repair pathway inhibitors.20,21

Impaired DNA damage repair is a common tumor vulnerability in patients with pancreatic cancer. The POLO trial demonstrates improved progression-free survival with maintenance olaparib in a subset of these patients who carried a germline BRCA1 or BRCA2 mutation and received at least 4 months of platinum-based chemotherapy without disease progression. These data are relevant to our treatment of patients today and point to the need for research and clinical trials to exploit this important vulnerability in additional patients with this difficult disease. 

Dr. Wolpin is Chief, Division of Gastrointestinal Oncology; Director, Hale Family Center for Pancreatic Cancer Research; and Director, Dana-Farber Cancer Institute–Lustgarten Foundation Dedicated Pancreatic Cancer Laboratory at Dana-Farber Cancer Institute and Harvard Medical School in Boston.

DISCLOSURE: Dr. Wolpin has received grant support from Celgene and Eli Lilly and has served as a consultant with BioLineRx, Celgene, GRAIL, and G1 Therapeutics.

REFERENCES

1. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2019.

2. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX vs gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011.

3. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.

4. Bailey P, Chang DK, Nones K, et al: Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531:47-52, 2016.

5. Cancer Genome Atlas Research Network: Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32:185-203.e13, 2017.

6. Lowery MA, Jordan EJ, Basturk O, et al: Real-time genomic profiling of pancreatic ductal adenocarcinoma. Clin Cancer Res 23:6094-6100, 2017.

7. Aguirre AJ, Nowak JA, Camarda ND, et al: Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov 8:1096-1111, 2018.

8. Pishvaian MJ, Bender RJ, Halverson D, et al: Molecular profiling of patients with pancreatic cancer. Clin Cancer Res 24:5018-5027, 2018.

9. Yurgelun MB, Chittenden AB, Morales-Oyarvide V, et al: Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med 21:213-223, 2019.

10. Hu C, Hart SN, Polley EC, et al: Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 319:2401-2409, 2018.

11. Gourley C, Balmaña J, Ledermann JA, et al: Moving from poly (ADP-ribose) polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy. J Clin Oncol 37:2257-2269, 2019.

12. 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 33:244-250, 2015.

13. Shroff RT, Hendifar A, McWilliams RR, et al: Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precis Oncol. May 16, 2018 (early release online).

14. O’Reilly EM, Lee JW, Lowery MA, et al: Phase I trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts. Cancer 124:1374-1382, 2018.

15. Tempero MA, Malafa MP, Chiorean EG, et al: Pancreatic adenocarcinoma, version 1.2019. J Natl Compr Canc Netw 17:202-210, 2019.

16. Stoffel EM, McKernin SE, Brand R, et al: Evaluating susceptibility to pancreatic cancer: ASCO provisional clinical opinion. J Clin Oncol 37:153-164, 2019.

17. Singhi AD, George B, Greenbowe JR, et al: Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology 156:2242-2253.e4, 2019.

18. Le DT, Durham JN, Smith KN, et al: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409-413, 2017.

19. Drilon A, Laetsch TW, Kummar S, et al: Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 378:731-739, 2018.

20. Polak P, Kim J, Braunstein LZ, et al: A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet 49:1476-1486, 2017.

21. Hill SJ, Decker B, Roberts EA, et al: Prediction of DNA repair inhibitor response in short-term patient-derived ovarian cancer organoids. Cancer Discov 8:1404-1421, 2018.


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