BRCA-mutated advanced pancreatic carcinoma

An unexpected new standard treatment

James Fleck: Anticancerweb 02(02), 2020

The most recent epidemiological data published by American Cancer Society in 2019, revealed pancreatic carcinoma as the forth cause of cancer death in USA. Most of the cases are diagnosed as locally advanced (29%) or metastatic disease (52%), respectively leading to a dismal 12% and 3% five-year survival rate. Metastatic pancreatic cancer has historically been refractory to systemic treatment. The ACCORD phase III trial randomized a very selective group of chemotherapy naïve metastatic pancreatic cancer patients (PS 0 or 1 and serum bilirubin < 1.5 times the upper normal limit) to receive FOLFIRINOX or gemcitabine. The trial was stopped earlier due to the superiority of the combined approaching (RR: 32% versus 9%, PFS: 6.4 months versus 3.3 months and OS: 11.1 months versus 6.8 months). Despite the significant increase in the outcomes, the median overall survival was still less than one year.  

Advances would come from next-generation sequencing of new genomic and/or targeted markers. Loss-of-function BRCA1/2 or PALB2 (gBRCA-PALB2+) germline mutations were related to an increased risk of pancreatic ductal adenocarcinoma (PDAC), which have been observed in as much as 9% of the patients. Since BRCA genes code for proteins enrolled in homologous recombination repair of DNA double-strand breaks, the mutated phenotype elicits an ineffective DNA repair and an increasing sensitivity to platinum-based chemotherapy. Pancreatic cancer-BRCA-mutated cells are also sensitive to PARP (poly-adenosine diphosphate-ribose polymerase) inhibitors. Trapping PARP in DNA single-strand breaks, generates DNA double-strand breaks in replicating tumor cells, which were already harboring a deficiency in homologous recombination repair process. The POLO double-blinded, placebo-controlled, phase III trial enrolled 154 BRCA-mutated metastatic PDAC patients that had not progressed during at least 16 weeks of first-line platinum-based chemotherapy. Patients were randomized in a 3:2 ratio to receive maintenance therapy with the  PARP inhibitor olaparib or placebo. The PFS was significant longer in the olaparib arm (7.4 months versus 3.8 months HR=0.53, P=0.004). Interim analysis at a data maturity of 46% revealed a longer median overall survival rate in both arms (18.9 months in olaparib arm and 18.1 months in placebo arm HR=0.91 P=0.68), confirming that BRCA germline mutation is a prognostic marker for metastatic PDAC.

Recently, the utility of concurrent/sequential use of PARP inhibitors have been well stablished in BRCA-mutated breast and ovarian cancer. A phase I multicenter trial using concurrent cisplatin, gemcitabine and veliparib in BRCA-germline mutation carriers-PDAC showed a unprecedent 78% RR and a median overall survival of 23.3 months. In January 24th, 2020 the Journal of Clinical Oncology published a multicenter randomized phase II trial designed to investigate the benefit of the addition of veliparib to the doublet (cisplatin + gemcitabine) as first-line treatment of gBRCA-PALB2+ PDAC. Two and three-year survival rate for the entire cohort were respectively 30.5% and 17.8%, confirming the better prognosis of this particular PDAC phenotype.

Additionally, the trial showed a disease control rate (DCR) of 100% favoring exclusive chemotherapy doublet (CD) use versus the combined use of veliparib + CD (DCR=78.3% P=0.02). This unexpected outcome was associated with a better therapeutic index, making the doublet cisplatin + gemcitabine a temporary new standard treatment for gBRCA-PALB2+ PDAC.

Abbreviations: USA = United States of America, PS = Performance status (ECOG), FOLFIRINOX = Oxaliplatin + Leucovorin + Irinotecan + Fluorouracil, RR = Response Rate, PFS = Progression-free Survival, OS = Overall Survival



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Thierry Conroy, Françoise Desseigne, Marc Ychou, et al: FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer, N Engl J Med 364:1817-25, 2011

Talia Golan, Pascal Hammel, Michele Reni, et al: Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer, N Engl J Med 381(4): 317–327, 2019 

Eileen M. O’Reilly, Jonathan W. Lee, Maeve A. Lowery, et al: Phase I Trial Evaluating Cisplatin, Gemcitabine and Veliparib in Two Patient Cohorts: Germline-BRCA Mutation Carriers and BRCA Wild-Type Pancreas Ductal Adenocarcinoma, Cancer 124(7): 1374–1382, 2018

Eileen M. O’Reilly, Jonathan W. Lee, Mark Zalupski, et al: Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin with or without Veliparib in Patients with Pancreas Adenocarcinoma and a Germline BRCA/ PALB2 Mutation, J Clin Oncol January 24th, 2020 DOI https://doi. org/10.1200/JCO.19. 02931

Photo by Jeremy Cai on Unsplash