New Applications for Chemotherapy, PARP Inhibitors Drive Progress in Pancreatic Cancer

Andrea Wang-Gillam, MD, PhD,

Although chemotherapy remains the cornerstone of treatment in pancreatic ductal adenocarcinoma, the field has begun to carve out more personalized approaches evidenced by the POLO trial, said Andrea Wang-Gillam, MD, PhD, who emphasized the importance of recommending patients for clinical trials whenever possible to continue moving the needle forward.

Findings from the ACCORD and MPACT study established FOLFIRINOX and the combination of gemcitabine and nab-paclitaxel (Abraxane) as frontline standards of care in metastatic pancreatic cancer, respectively. However, apart from the alterative dosing and scheduling strategies that had been evaluated, limited progress had been made for the better part of the following decade, explained Wang-Gillam.

“It’s quite humbling because the data [with FOLFIRINOX] was presented in 2010, and now it’s 2020, and our regimen hasn’t changed,” said Wang-Gillam, an associate professor in the Division of Oncology at Washington University in St. Louis, Missouri, in a presentation during a 2020 Institutional Perspectives in Cancer webinar on gastrointestinal malignancies.

As such, the field looked for ways to improve upon established chemotherapy regimens. To that end, investigators launched a phase 1/2 trial (NCT02551991), which evaluated liposomal irinotecan (Onivyde)––an FDA-approved agent for patients with metastatic pancreatic adenocarcinoma following disease progression on gemcitabine-based therapy––plus 5-fluorouracil (5-FU)/leucovorin and oxaliplatin (NALIRIFOX)––as frontline therapy.

The results showed an objective response rate of 34.4% and a disease-control rate of 71.9%. The median progression-free survival (PFS) and overall survival (OS) was 9.2 months and 12.6 months, respectively.¹

In June 2020, the FDA granted a fast track designation to NALIRIFOX for patients with previously untreated, unresectable, locally advanced or metastatic pancreatic ductal adenocarcinoma.

Findings from the study also served as the basis for the international, phase 3 NAPOLI-3 study (NCT04083235), which is evaluating the efficacy and safety of NALIRIFOX versus gemcitabine and nab-paclitaxel as a first-line treatment for patients with metastatic pancreatic cancer.

“This trial is ongoing, and I recommend that all patients [who are eligible] participate in the study,” said Wang-Gillam.

Although chemotherapy has retained its role in the frontline setting, findings from the phase 3 POLO trial demonstrated that maintenance therapy with olaparib (Lynparza) should be integrated into the paradigm. In the trial, patients who had been on frontline platinum-based chemotherapy for at least 16 weeks were randomized to olaparib or placebo. Results showed that the median PFS was 7.4 months with olaparib versus 3.8 months with placebo.² However, in updated findings presented at the 2021 Gastrointestinal Cancers Symposium, the median OS was 19.0 months with olaparib and 19.2 months with placebo (HR, 0.83; 95% CI, 0.56-1.22; P = .3487).³

In December 2019, the FDA approved the PARP inhibitor as maintenance therapy for patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Subsequently, the NCCN endorsed germline testing for all patients with pancreatic ductal adenocarcinoma.

“It’s still a very narrow patient population [who harbors BRCA1/2 mutations], but overall [germline testing] definitely needs to be done [in our patients],” said Wang-Gillam.

Chemotherapy has also been utilized in the neoadjuvant setting, explained Wang-Gillam, who cited evidence from the phase 3 PREOPANC study showing improved disease-free survival and OS with neoadjuvant radiochemotherapy versus immediate surgery in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma.⁴

Findings from the phase 2 ESPAC-5F provided further evidence in support of neoadjuvant chemotherapy in patients with borderline resectable disease, with a 1-year OS rate of 77% and 42% with neoadjuvant therapy and up-front surgery, respectively (HR, 0.28; 95% CI, 0.14-0.57; P < .001).⁵

“It’s well accepted by the community, [especially] in large academic centers that neoadjuvant therapy is the more favorable approach to improve outcomes,” said Wang-Gillam.

In conclusion, Wang-Gillam called attention to the phase 2 SWOG 1505 trial, which was designed to determine the optimal neoadjuvant chemotherapy regimen. In the trial, patients with a resectable primary tumor on CT or MRI were randomized to modified FOLFIRINOX every 2 weeks for 6 cycles or gemcitabine plus nab-paclitaxel for 3 weeks on and 1 week off for 9 cycles, followed by restaging, surgery, and an additional 12 weeks of treatment.

The primary end point of 2-year OS was 41.6% in the modified FOLFIRINOX arm versus 48.8% in the gemcitabine/nab-paclitaxel arm, failing to show the superiority of either regimen⁶, said Wang-Gillam.

References

1. Wainberg ZA, Bekaii-Saab T, Boland PM, et al. First-line liposomal irinotecan 5 fluorouracil/leucovorin oxaliplatin in patients with pancreatic ductal adenocarcinoma: Primary analysis from a phase 1/2 study. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 1-4, 2020; virtual. Abstract LBA-001.
2. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. doi:10.1056/NEJMoa1903387
3. Golia T, Hammel P, Reni M, et al. Overall survival from the phase 3 POLO trial: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol. 2021;39(suppl; abstr 378).
4. Van Tienhoven G, Versteijne E, Suker M, et al. Preoperative chemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial. J Clin Oncol. 2018;36(suppl 18):LBA4002. doi:10.1200/JCO.2018.36.18_supplLBA4002
5. Ghaneh P, Palmer DH, Cicconi S, et al. ESPAC-5F: four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer. J Clin Oncol. 2020;38(suppl 15):4505. doi:10.1200/JCO.2020.38.15_suppl.4505
6. Sohal D, Duong MT, Ahmad SA, et al. SWOG S1505: results of perioperative chemotherapy (peri-op CTx) with mFOLFIRINOX versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA). 2020;38(suppl 15):4504. doi:10.1200/JCO.2020.38.15_suppl4504