Pancreatic cancer remains one of the most difficult-to-treat cancer types. Although there have been some advances in the past few years, the needle has not moved much on survival and prognosis.
An important issue for those patients with metastatic pancreatic cancer who respond to front-line chemotherapy is whether maintenance therapy for BRCA-mutated metastatic pancreatic cancer should be with a poly (ADP-ribose) polymerase (PARP) inhibitor or continued chemotherapy. Shubham Pant, MD, of The University of Texas MD Anderson Cancer Center, Houston, tackled this subject during the virtual edition of the 2020 Chemotherapy Foundation Symposium.1
Shubham Pant, MD
The standard of care for metastatic pancreatic cancer is FOLFIRINOX (leucovorin, fluorouracil [5-FU], irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel. These regimens offer patients a median progression-free survival of about 6 months and a median overall survival ranging from 8 months to 1 year. Less than 50% of patients with metastatic pancreatic cancer live long enough to receive second-line treatment, he commented.
“No targeted treatments for a biomarker-selected population of patients with pancreatic cancer had been validated by phase III trials until November 2019,” Dr. Pant told the audience. “The international POLO trial was the first randomized phase III trial to validate a targeted treatment in a biomarker-selected population of patients with pancreatic cancer.”
The PARP inhibitor olaparib was approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic pancreatic cancer whose disease has not progressed after at least 16 weeks on first-line chemotherapy. Approval was based on the results of the POLO trial, which enrolled patients with a germline mutation in BRCA1 and BRCA2.2
POLO was a randomized, double-blind, placebo-controlled phase III trial that screened 3,315 patients at 119 centers on 4 continents for germline BRCA mutations. Patients who were BRCA-positive were treated with at least 16 weeks of front-line platinum-based chemotherapy. Those who did not experience disease progression (n = 154) were randomly assigned in a 3:2 ratio to receive either maintenance olaparib at 300 mg twice daily or placebo. Treatment continued until radiographically detected disease progression.
Progression-free survival, the primary endpoint, was 7.4 months with olaparib vs 3.8 months with placebo—representing a 47% improvement with olaparib (P = .0038). These results were hailed as practice-changing. However, overall survival was not mature at the time of the interim analysis. No new safety concerns were raised for olaparib in the study; however, more patients treated with olaparib experienced fatigue and nausea, whereas other side effects were similar between the treatment arms.
“Olaparib is not without side effects, which may include nausea, fatigue, abdominal pain, as well as hematologic toxicity. Patients on this drug may need dose adjustments,” Dr. Pant commented.
Dr. Pant reminded listeners that current guidelines from both ASCO and the National Comprehensive Cancer Network® recommend germline testing for any patient with pancreatic cancer. “We think testing will give patients options,” he said. “We recommend early germline testing for patients who are likely to be candidates for therapy.”
PRODIGE 35-PANOPTIMOX Trial
The first nontargeted option for maintenance therapy in metastatic pancreatic cancer was FOLFIRINOX, which was evaluated in the PRODIGE 35-PANOPTIMOX trial.3 In this three-arm study, 273 patients with metastatic pancreatic cancer were randomly assigned to receive 6 months of FOLFIRINOX (arm A, n = 91), 4 months of FOLFIRINOX followed by leucovorin/5-FU maintenance (arm B, n = 92), or alternating gemcitabine and FOLFIRI.3 every 2 months (arm C, n = 90).
The 6-month progression-free survival rate was 47% in arm A, 44% in arm B, and 34% in arm C; median progression-free survival was 6.3 months, 5.7 months, and 4.5 months, respectively. Median overall survival was 10.1 months, 11.2 months, and 7.3 months, respectively.
These results suggested that OPTIMOX-like induction maintenance therapy, eliminating oxaliplatin after 4 months and avoiding greater toxicity associated with continued oxaliplatin, is a viable treatment strategy for metastatic pancreatic cancer. In addition, they showed that a gemcitabine/FOLFIRI approach was not as effective.
“We recommend early germline testing for patients who are likely to be candidates for therapy.”— Shubham Pant, MD
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“Metastatic pancreatic cancer is an aggressive disease. It is rare to discontinue all therapy after 16 weeks of chemotherapy. Maintenance therapy is usually used,” Dr. Pant noted.
Dr. Pant presented a hypothetical case of a 55-year-old woman with metastatic pancreatic cancer and a germline BRCA2 mutation who responded well to first-line FOLFIRINOX for at least 4 months. He gave the audience three choices: continue with FOLFIRINOX, switch to capecitabine, or switch to olaparib. He said all of them are options for patients with metastatic pancreatic cancer, noting patients should be followed for toxicity.
“Continued FOLFIRINOX, capecitabine, or olaparib are all options for maintenance therapy. The story is still evolving,” stated Dr. Pant.
DISCLOSURE: Dr. Pant has received honoraria from 4D Pharma; has served as a consultant or advisor to Tyme Technologies, Xencor, and Zymeworks; and has received institutional research funding from ArQule, Astellas Pharma, Bristol Myers Squibb, Five Prime Therapeutics, GlaxoSmithKline, Ipsen, Lilly, Mirati Therapeutics, Novartis, Onco Response, RedHill Biopharma, Rgenix, sanofi-aventis, and Xencor.
REFERENCES
1. Pant S: Maintenance therapy in BRCA-mutated pancreatic cancer: PARP inhibitor or continued chemotherapy? 2020 Chemotherapy Foundation Symposium. Presented November 6, 2020.
2. 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.
3. Dahan L, Phelip JM, Le Malicot K, et al: FOLFIRINOX under progression, FOLFIRINOX with maintenance treatment, or sequential treatment with gemcitabine plus FOLFIRI.3 for first-line treatment of metasatic pancreatic cancer: A randomized phase II trial (PRODIGE 35-PANOPTIMOX). 2018 ASCO Annual Meeting. Abstract 4000. Presented June 4, 2018.
